bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mast cell regranulation involves a metabolic switch promoted by the interaction between mTORC1 and a glucose-6-phosphate transporter
Authors: Iskarpatyoti Jason A , Shi Jianling , Rathor Abhay P S , Miao Yuxuan , Abraham Soman N 
Published: October 2021

AbstractMast cells (MCs) are highly granulated tissue resident hematopoietic cells and because of their capacity to degranulate and release many proinflammatory mediators, they are major effectors of chronic inflammatory disorders including asthma and urticaria. As MCs have the unique capacity to reform their granules following degranulationin vitro,their potential to undergo multiple cycles of degranulation and regranulationin vivohas been linked to their pathogenesis. However, it is not known what factors regulate MC regranulation let alone if MC regranulation occursin vivo. Here, we report that IgE-sensitized mice can undergo multiple bouts of regranulation, following repeated anaphylactic reactions. mTORC1, a critical nutrient sensor that activates protein and lipid synthesis, was found necessary for MC regranulation. mTORC1 activity in MCs was regulated by a glucose-6-phosphate transporter, Slc37a2, which was found to be necessary for increased glucose-6-phosphate and ATP levels during regranulation, two upstream signals of mTOR. Slc37a2 is highly expressed at the cell periphery early during regranulation where it appears to colocalize with mTORC1. Additionally, this transporter was found to concentrate extracellular metabolites within endosomes which are trafficked directly into nascent granules. Thus, the metabolic switch associated with MC regranulation is mediated by the interactions of a cellular metabolic sensor and a transporter of extracellular metabolites into MC granules.
Impact of Antibody Cocktail Therapy Combined with Casirivimab and Imdevimab on Clinical Outcome for Covid-19 patients in A Real-Life Setting: A Single Institute Analysis
Authors: Kakinoki Yasutaka , Yamada Kazuki , Tanino Yoko , Suzuki Keiko , Ichikawa Takaya , Suzuki Naoki , Asari Go , Nakamura Ai , Kukita Shin , Uehara Akito , Saito Seisuke , Kuroda Shohei , Sakagami Hidemitsu , Nagashima Yuuki , Takahashi Kae , Suzuki Satoshi 
Published: October 2021

ABSTRACTBackgroundRecent data from clinical trial suggest that antibody cocktail therapy, a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to rapidly reduce the viral load and markedly decrease the risk of hospitalization or death among high-risk patients with coronavirus disease 2019 (Covid-19). However, it remains unclear how effective in a real-life clinical setting the therapy is.MethodsWe retrospectively analyzed mild to moderate Covid-19 patients with one or more high-risk factors for severe disease who consecutively underwent the antibody cocktail therapy of the disease in our institute in June 2021 through early September 2021, compared to those with high-risk factors who were isolated in non-medical facilities consecutively during the same period, thereby being not given the antibody cocktail therapy there. The key outcome was the percentage of patients with Covid-19-related deterioration which needed additional medical interventions, such as oxygen support or other antiviral therapies.ResultsData from 55 patients with initially receiving antibody cocktail therapy and 53 patients with isolation into non-medical facilities are analyzed. 22 (41.5 %) of 53 patients with isolation facilities were finally hospitalized to receive medical interventions. On the other hand, 13 (23.6 %) of 55 patients with antibody cocktail therapy in our hospital subsequently underwent further medical interventions because of the progression. In multivariate analysis with variables of age, BMI, and high-risk factors, the antibody cocktail therapy significantly reduced 70 % in the need for further medical interventions compared to the initial isolation in the non-medical facilities (odds ratio=0.30, 95%CI [0.10-0.87], p=0.027). Furthermore, patients with 96% or above of SPO2 were significantly more favorable for the therapy than those with 95% or below of SPO2.ConclusionThe treatment of antibody cocktail was closely linked to reduction in the need for further medical interventions. The result indicates that the antibody cocktail therapy is associated with reducing the strain on hospitals, which is related to the improvement of medical management for public health care in Covid-19 pandemic era.
Current surgical practice for children born with a cleft lip and/or palate in the United Kingdom
Authors: Fell Matthew , Davies Alex , Davies Amy , Chummun Shaheel , Cobb Alistair R.M. , Moar Kanwalraj , Wren Yvonne 
Published: October 2021

ABSTRACTBackgroundThis study describes primary surgical reconstructions performed for children born with a cleft lip and/or palate in the United Kingdom.MethodsData were obtained from the Cleft Collective, a national longitudinal cohort study. Data forms completed at the time of surgery included details on timing, technique and adjuncts used during the operative period. Demographic data on participants were validated via parental questionnaires.ResultsBetween 2015 and 2021, 1782 Cleft Collective surgical forms were included, relating to the primary reconstructions of 1514 individual children. The median age at primary cheiloplasty was 4.3 months. Unilateral cleft lips were reconstructed with an anatomical subunit approximation technique in 53%, whereas bilateral cleft lips were reconstructed with a broader range of eponymous techniques. Clefts of the soft palate were reconstructed at a median age of 10.3 months with an intravelar veloplasty in 94% cases. Clefts of the hard palate were reconstructed with a vomer flap in 84% cases in a bi-modal age distribution, relating to reconstruction carried out simultaneously with either lip or soft palate reconstruction. Antibiotics were used in 96% of cases, with an at-induction-only regimen used more commonly for cheiloplasties (p<0.001) and a 5–7day post-operative regime used more commonly for soft palatoplasties (p<0.001). Peri-operative steroids were used more commonly in palatoplasties than cheiloplasties (p<0.001) but tranexamic acid use was equivalent (p=0.73).ConclusionThis study contributes to our understanding of current cleft surgical pathways in the United Kingdom and will provide a baseline for analysis of the effectiveness of utilised protocols.
New markers for qPCR detection of the dinoflagellate Alexandrium catenella in Chile
Authors: Espinoza Javiera , Yarimizu Kyoko , Nagai Satoshi , Espinoza-González Oscar , Guzman Leonardo , Fuenzalida Gonzalo 
Published: October 2021

AbstractAlexandrium catenella (Whedon & Kofoid) is a dinoflagellate known as a primary source of paralytic shellfish poisoning in Chile. The distribution range of harmful algal blooms generated by this species has extended during the last decades, and the frequency of these events has increased. In this work, we developed TaqMan markers from Chilean strains that can be used to identify and quantify through qPCR, which can be implemented in monitoring programs for the early detection of this species.
Investigating the growth of an engineered strain of Cyanobacteria with an Agent-Based Model and a Recurrent Neural Network
Authors: Sakkos Jonathan , Weaver Joe , Robertson Connor , Li Bowen , Taniguchi Denis , Maheshwari Ketan , Ducat Daniel , Zuliani Paolo , McGough Andrew Stephen , Curtis Tom , Fuentes-Cabrera Miguel 
Published: October 2021

AbstractA computational framework combining Agent-Based Models (ABMs) and Deep Learning techniques was developed to help design microbial communities that convert light and CO2 into useful bioproducts. An ABM that accounts for CO2, light, sucrose export rate and cell-to-cell mechanical interactions was used to investigate the growth of an engineered sucrose-exporting strain of Synechococcus elongatus PCC 7942. The ABM simulations produced population curves and synthetic images of colony growth. The curves and the images were analyzed, and growth was correlated to nutrients availability and colonies’ initial spatial distribution. To speed up the ABM simulations, a metamodel based on a Recurrent Neural Network, RNN, was trained on the synthetic images of growth. This metamodel successfully reproduced the population curves and the images of growth at a lower computational cost. The computational framework presented here paves the road towards designing microbial communities containing sucrose-exporting Synechococcus elongatus PCC 7942 by exploring the solution space in silico first.
A theoretical framework for proteome-scale single-molecule protein identification using multi-affinity protein binding reagents
Authors: Egertson Jarrett D. , DiPasquo Dan , Killeen Alana , Lobanov Vadim , Patel Sujal , Mallick Parag 
Published: October 2021

AbstractThe proteome is perhaps the most dynamic and valuable source of functional biological insight. Current proteomic techniques are limited in their sensitivity and throughput. A typical single experiment measures no more than 8% of the human proteome from blood or 35% from cells and tissues 1, 2. Here, we introduce a theoretical framework for a fundamentally different approach to proteomics that we call Protein Identification by Short-epitope Mapping (PrISM). PrISM utilizes multi-affinity reagents to target short linear epitopes with both a high affinity and low specificity. PrISM further employs a novel protein decoding algorithm that considers the stochasticity expected for single-molecule binding. In simulations, PrISM is able to identify more than 98% of proteins across the proteomes of a wide range of organisms. PrISM is robust to potential experimental confounders including false negative detection events and noise. Simulations of the approach with a chip containing 10 billion protein molecules show a dynamic range of 11.5 and 9.5 orders of magnitude for blood plasma and HeLa cells, respectively. If implemented experimentally, PrISM stands to rapidly quantify over 90% of the human proteome in a single experiment, potentially revolutionizing proteomics research.
Superresolution microscopy reveals partial preassembly and subsequent bending of the clathrin coat during endocytosis
Authors: Mund Markus , Tschanz Aline , Wu Yu-Le , Frey Felix , Mehl Johanna L. , Kaksonen Marko , Avinoam Ori , Schwarz Ulrich S. , Ries Jonas 
Published: October 2021

AbstractEukaryotic cells use clathrin-mediated endocytosis to take up a large range of extracellular cargos. During endocytosis, a clathrin coat forms on the plasma membrane, but it remains controversial when and how it is remodeled into a spherical vesicle.Here, we use 3D superresolution microscopy to determine the precise geometry of the clathrin coat at large numbers of endocytic sites. Through pseudo-temporal sorting, we determine the average trajectory of clathrin remodeling during endocytosis. We find that clathrin coats assemble first on flat membranes to 50% of the coat area, before they become rapidly and continuously bent, and confirm this mechanism in three cell lines. We introduce the cooperative curvature model, which is based on positive feedback for curvature generation. It accurately describes the measured shapes and dynamics of the clathrin coat and could represent a general mechanism for clathrin coat remodeling on the plasma membrane.
Localization of the putative recombinase Pf-int to the apicoplast of Plasmodium falciparum
Authors: Berglar A. V. , Vembar S. S. , Gopaul D. N. 
Published: October 2021

AbstractDiseases caused by apicomplexan parasites, such as malaria and toxoplasmosis cause ∼200 million (worldwide) and 1 million (Europe) infections, respectively, every year. Apicomplexa possess a non-photosynthetic organelle homologous to the plant chloroplast, the so-called apicoplast, that is essential for their growth and survival. This study focused on the Int recombinase, the first protein discovered in Plasmodium spp. with the features of a site-specific recombinase, and which has an apicoplast targeting leader sequence at its amino-terminus. Int is conserved amongst several apicomplexan parasites. In the human toxoplasmosis parasite, Toxoplasma, Int localizes to the apicoplast and Pf-Int, the P. falciparum member, belongs to the group of non-mutable essential genes in P. falciparum. A conserved protein that has been shown to be essential at least in one species and that localizes to an essential organelle may become a novel drug target. Therefore, the aim of this study was to confirm the sub-cellular localization of Int in the human malaria parasite P. falciparum. Using western blot analysis and immunofluorescence microscopy of P. falciparum asexual blood stages, we observed that Int partially co-localized with the apicoplast (to discrete foci adjacent to the nucleus).
New from old: discovery of the novel antibiotic actinomycin L in Streptomyces sp. MBT27
Authors: Machushynets Nataliia , Elsayed Somayah S. , Du Chao , Siegler Maxime A. , de la Cruz Mercedes , Genilloud Olga , Hankemeier Thomas , van Wezel Gilles P. 
Published: October 2021

ABSTRACTStreptomycetes are major producers of bioactive natural products, including the majority of the antibiotics. While much if the low-hanging fruit has been discovered, it is predited that less than 5% of the chemical space has been mined. Here, we describe the novel actinomycins L1 and L2, which are produced by Streptomyces sp. MBT27. The molecules were discovered via metabolic analysis combined with molecular networking of cultures grown with different combinations of carbon sources. Actinomycins L1 and L2 are diastereoisomers, and the structure of actinomycin L2 was resolved using NMR and single crystal X-ray crystallography. Actinomycin L is formed via a unique spirolinkage of anthranilamide to the 4-oxoproline moiety of actinomycin X2, prior to the condensation of the actinomycin halves. Feeding anthranilamide to cultures of Streptomyces antibioticus, which has the same biosynthetic gene cluster as Streptomyces sp. MBT27 but only produces actinomycin X2, resulted in the production of actinomycin L. This shows that actinomycin L results from joining two distinct metabolic pathways, namely those for actinomycin X2 and for anthranilamide. Actinomycins L1 and L2 showed significant antimicrobial activity against Gram- positive bacteria. Our work shows how new molecules can still be identified even in the oldest of natural product families.IMPORTANCEActinomycin was the first antibiotic discovered in an actinobacterium by Selman Waksman and colleagues, as early as 1940. This period essentially marks the start of the ‘golden era’ of antibiotic discovery. Over time, emerging antimicrobial resistance (AMR) and the declining success rate of antibiotic discovery resulted in the current antibiotic crisis. We surprisingly discovered that under some growth conditions, Streptomyces sp. MBT27 can produce actinomycins that are significantly different from those that have been published so far. The impact of this work is not only that we have discovered a novel molecule with very interesting chemical modifications in one of the oldest antibiotics ever described, but also that this requires the combined action of primary and secondary metabolic pathways, namely the biosynthesis of anthranilamide and of actinomycin X2, respectively. The implication of the discovery is that even the most well-studied families of natural products may still have surprises in store for us.
SLX4 dampens MutSα-dependent mismatch repair
Authors: Guervilly Jean-Hugues , Blin Marion , Laureti Luisa , Baudelet Emilie , Audebert Stéphane , Gaillard Pierre-Henri 
Published: October 2021

ABSTRACTThe tumour suppressor SLX4 plays multiple roles in the maintenance of genome stability, acting as a scaffold for structure-specific endonucleases and other DNA repair proteins. It directly interacts with the mismatch repair (MMR) protein MSH2 but the significance of this interaction remained unknown until recent findings showing that MutSβ (MSH2-MSH3) stimulates in vitro the SLX4-dependent Holliday junction resolvase activity. Here, we characterize the mode of interaction between SLX4 and MSH2, which relies on an MSH2-interacting peptide (SHIP box) that drives interaction of SLX4 with both MutSβ and MutSα (MSH2-MSH6). While we show that this MSH2 binding domain is dispensable for the well-established role of SLX4 in interstrand crosslink repair, we find that it mediates inhibition of MutSα-dependent MMR by SLX4, unravelling an unanticipated function of SLX4.
Altered Cardiolipin Metabolism is Associated with Cardiac Mitochondrial Dysfunction in Pulmonary Vascular Remodeled Perinatal Rat Pups
Authors: Cole Laura K. , Sparagna Genevieve C. , Dolinsky Vernon W. , Hatch Grant M. 
Published: October 2021

AbstractBackgroundPulmonary vascular remodeling (PVR)in uteroresults in the development of heart failure (HF). The alterations that occur in cardiac lipid and mitochondrial bioenergetics during the development ofin uteroPVR was unknown.MethodsPVR was induced in pupsin uteroby exposure of pregnant dams to indomethacin and hypoxia. Cardiac lipids, echocardiographic function and cardiomyocyte mitochondrial function were subsequently examined.ResultsPerinatal rat pups with PVR exhibited elevated left and right cardiac ventricular internal dimensions and reduced ejection fraction and fractional shortening compared to controls. Cardiac myocytes from these pups exhibited increased glycolytic capacity and glycolytic reserve compared to controls. However, respiration with glucose as substrate was unaltered. Fatty acid oxidation and ATP-insensitive respiration were increased in isolated cardiac myocytes from these pups compared to controls indicating mitochondrial dysfunction. Although abundance of mitochondrial respiratory complexes were unaltered, increased trilinoleoyl-lysocardiolipin levels in these pups was observed. A compensatory increase in both cardiolipin (CL) and phosphatidylethanolamine (PE) content were observed due to increased synthesis of these phospholipids.ConclusionAlterations in cardiac cardiolipin and phospholipid metabolism in PVR rat pups is associated with the mitochondrial bioenergetic and cardiac functional defects observed in their hearts.Impact statement- Phospholipid metabolism was examined in pulmonary vascular remodeling in perinatal rat pups.- Pulmonary vascular remodeling was inducedin uteroby treating pregnant dams with hypoxia and indomethacin at 19-21 days of gestation.- The offspring exhibited altered pulmonary arterial remodeling with subsequent cardiac hypertrophy, ventricular dysfunction, cardiac myocyte mitochondrial dysfunction with altered fatty acid utilization.- In addition, the offspring exhibited elevated cardiolipin, lysocardiolipin and phosphatidylethanolamine content which may potentially contribute to the cardiac mitochondrial dysfunction.
Dietary Proanthocyanidins Exert Localized Immunomodulatory Effects in Porcine Pulmonary and Gastrointestinal Tissues duringAscaris suum-induced Type 2 inflammation
Authors: Andersen-Civil Audrey Inge Schytz , Myhill Laura J. , Gökgöz Nilay Büdeyri , Engström Marica T. , Mejer Helena , Zeller Wayne E. , Salminen Juha-Pekka , Krych Lukasz , Lauridsen Charlotte , Nielsen Dennis S. , Thamsborg Stig M. , Williams Andrew R. 
Published: October 2021

AbstractBioactive dietary components may considerably influence intestinal health and resistance to enteric disease. Proanthocyanidins (PAC) are dietary polyphenols with putative health-promoting activity that have been increasingly studied for their anti-inflammatory and immunomodulatory effects. However, whether dietary PAC can regulate type-2 immune function and inflammation at mucosal surfaces remains unclear. Here, we investigated whether diets supplemented with purified PAC modulated pulmonary and intestinal mucosal immune responses during infection with the helminth parasiteAscaris suumin pigs.A. suuminfection induced a type 2-biased immune response in lung and intestinal tissues, characterized by pulmonary granulocytosis, increased Th2/Th1 T cell ratios in tracheal-bronchial lymph nodes, intestinal eosinophilia, and modulation of genes involved in mucosal barrier function and immunity. We observed that PAC had only minor effects on pulmonary immune responses, regardless of concurrentA. suuminfection. However, RNA-sequencing of intestinal tissues revealed that dietary PAC significantly enhanced transcriptional responses related to immune function, antioxidant responses, and cellular stress activity, both in uninfected andA. suum-infected animals.A. suuminfection and dietary PAC both induced distinct changes in gut microbiota composition, primarily in the jejunum and colon, respectively. Notably, PAC substantially increasedLimosilactobacillus reuteriabundance in the colon of both naïve andA. suum-infected animals. Thus, dietary PAC may have distinct beneficial effects on intestinal health during infection with mucosal pathogens, whilst having limited activity to modulate naturally-induced type-2 pulmonary inflammation. Our results shed further light on the mechanisms underlying the health-promoting properties of PAC-rich foods, and may aid in the design of novel dietary supplements to regulate mucosal inflammatory responses in the gastrointestinal tract.
Recording of cellular physiological histories along optically readable self-assembling protein chains
Authors: Linghu Changyang , An Bobae , Shpokayte Monika , Celiker Orhan T. , Shmoel Nava , Zhang Chi , Park Won Min , Ramirez Steve , Boyden Edward S. 
Published: October 2021

AbstractObserving cellular physiological histories is key to understanding normal and disease-related processes, but longitudinal imaging is laborious and equipment-intensive. A tantalizing possibility is that cells could record such histories in the form of digital biological information within themselves, for later high-throughput readout. Here we show that this concept can be realized through information storage in the form of growing protein chains made out of multiple self-assembling subunits bearing different labels, each corresponding to a different cellular state or function, so that the physiological history of the cell can be visually read out along the chain of proteins. Conveniently, such protein chains are fully genetically encoded, and easily readable with simple, conventional optical microscopy techniques, compatible with visualization of cellular shape and molecular content. We use such expression recording islands (XRIs) to record gene expression timecourse downstream of pharmacological and physiological stimuli, in cultured neurons and in living mouse brain.