bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lignin impairs Cel7A degradation of cellulose by impeding enzyme movement and not by acting as a sink
Authors: Haviland Zachary K. , Nong Daguan , Zexer Nerya , Tien Ming , Anderson Charles T. , Hancock William O. 
Published: August 2023

AbstractBackgroundCellulose degradation by cellulases has been studied for decades due to the potential of using lignocellulosic biomass as a sustainable source of bioethanol. In plant cell walls, cellulose is bonded together and strengthened by the polyphenolic polymer, lignin. Because lignin is tightly linked to cellulose and is not digestible by cellulases, is thought to play a dominant role in limiting the efficient enzymatic degradation of plant biomass. Removal of lignin via pretreatments currently limits the cost-efficient production of ethanol from cellulose, motivating the need for a better understanding of how lignin inhibits cellulase-catalyzed degradation of lignocellulose. Work to date using bulk assays has suggested three possible inhibition mechanisms: lignin blocks access of the enzyme to cellulose, lignin impedes progress of the enzyme along cellulose, or lignin binds cellulases directly and acts as a sink.ResultsWe used single-molecule fluorescence microscopy to investigate the nanoscale dynamics of Cel7A fromTrichoderma reesei, as it binds to and moves along purified bacterial cellulose in vitro. Lignified cellulose was generated by polymerizing coniferyl alcohol onto purified bacterial cellulose, and the degree of lignin incorporation into the cellulose meshwork was analyzed by optical and electron microscopy. We found that Cel7A preferentially bound to regions of cellulose where lignin was absent, and that in regions of high lignin density, Cel7A binding was inhibited. With increasing degrees of lignification, there was a decrease in the fraction of Cel7A that moved along cellulose rather than statically binding. Furthermore, with increasing lignification, the velocity of processive Cel7A movement decreased, as did the distance that individual Cel7A molecules moved during processive runs.ConclusionsIn an in vitro system that mimics lignified cellulose in plant cell walls, lignin did not act as a sink to sequester Cel7A and prevent it from interacting with cellulose. Instead, lignin both blocked access of Cel7A to cellulose and impeded the processive movement of Cel7A along cellulose. This work implies that strategies for improving biofuel production efficiency should target weakening interactions between lignin and cellulose surface, and further suggest that nonspecific adsorption of Cel7A to lignin is likely not a dominant mechanism of inhibition.
Ferredoxin 1 is essential for embryonic development and lipid homeostasis
Authors: Mohibi Shakur , Zhang Yanhong , Perng Vivian , Chen Mingyi , Zhang Jin , Chen Xinbin 
Published: August 2023

AbstractMammalian ferredoxin 1 and 2 (FDX1/2) belong to an evolutionary conserved family of iron-sulfur cluster containing proteins and act as electron shutters between ferredoxin reductase (FDXR) and numerous proteins involved in critical biological pathways. FDX1 is involved in biogenesis of steroids and bile acids, Vitamin A/D metabolism, and lipoylation of tricarboxylic acid (TCA) cycle enzymes. FDX1 has been extensively characterized biochemically but its role in physiology and lipid metabolism has not been explored. In this study, we generatedFdx1-deficient mice and showed that knockout of both alleles of theFdx1gene led to embryonic lethality. We also showed that likeFdxr+/−mice,Fdx1+/−mice had a shorter life span and were prone to steatohepatitis. However, unlikeFdxr+/−mice,Fdx1+/−mice were not prone to spontaneous tumors. Additionally, we showed that FDX1 deficiency led to lipid droplet accumulation possibly via the ABCA1-SREBP1/2 pathway. Specifically, untargeted lipidomic analysis showed that FDX1 deficiency led to alterations in several classes of lipids, including cholesterol, triacylglycerides, acylcarnitines, ceramides, phospholipids and lysophospholipids. Taken together, our data indicate that FDX1 is essential for mammalian embryonic development and lipid homeostasis at both cellular and organismal levels.
rTMS to right parietal cortex decreases the precision of spatial priors in perceptual decision making
Authors: Zuanazzi Arianna , Meijer David , Noppeney Uta 
Published: August 2023

AbstractThroughout life human observers make perceptual decisions under uncertainty guided by prior knowledge about the world’s causal structure and properties. According to Bayesian probability theory, optimal decision making relies on integrating prior knowledge with current sensory inputs, weighted by their relative precisions (i.e., inverse of uncertainty). Thus, representing uncertainty is essential for optimal decisions. Although extensive research suggests that human perceptual decision making follows Bayesian principles, the neural underpinnings of priors and their uncertainties remain elusive. In this five-day study, we employed psychophysics, Bayesian causal inference models, and offline low-frequency (i.e., 1Hz) transcranial magnetic stimulation (TMS) to probe the role of right intraparietal sulcus (IPS), a key region for spatial processing, in the integration of prior knowledge with auditory/visual inputs for spatial decisions. Model-free and Bayesian modelling analyses consistently showed a reduction in the precision of observers’ long-term spatial prior and in the influence of their previous spatial choices on their current spatial decisions for right IPS-TMS compared to sham-TMS. In contrast, the causal prior and the auditory/visual uncertainties remained unaffected. The results show that offline IPS-TMS can selectively reduce the precision or influence of observers’ long-term spatial prior and their short-term spatial expectations on perceptual decisions, without affecting their causal prior or sensory uncertainties (i.e., likelihood). Our findings provide causal evidence for the role of parietal cortex, situated at the top of the audiovisual spatial processing hierarchy, in encoding the uncertainty of spatial - but not causal - priors during perceptual decision-making.Significance statementPerceptual decisions under uncertainty are pervasive in everyday life. Substantial evidence suggests that humans perform perceptual decisions near-optimally. They combine sensory inputs with prior knowledge about the signals’ causal structure and locations weighted by their uncertainties. Yet, the neural underpinnings remain elusive. Combining psychophysics, Bayesian models, and offline low-frequency inhibitory transcranial magnetic stimulation (TMS), we provide causal evidence that the parietal cortex is crucial for encoding the uncertainty of spatial - but not causal - priors during perceptual decision-making. Intriguingly, observers relied less on their long-term and short-term prior spatial expectations after parietal-TMS, as compared to sham-TMS. These results provide important insights into the neural substrates of priors and their uncertainties as key ingredients for near-optimal decisions consistent with normative Bayesian principles.
A simple solid media assay for detection of synergy between bacteriophages and antibiotics
Authors: Khong Ethan , Oh Joseph , Jimenez Julian M. , Liu Roland , Dunham Sage , Monsibais Alisha , Rhoads Alison , Ghatbale Pooja , Garcia Andrew , Cobián Güemes Ana Georgina , Blanc Alisha N. , Chiu Megan , Kuo Peiting , Proost Marissa , Kline Ahnika , Aslam Saima , Schooley Robert T. , Whiteson Katrine , Fraley Stephanie I. , Pride David T. 
Published: August 2023

ABSTRACTThe emergence of antibiotic resistant bacteria (ARB) has necessitated the development of alternative therapies to deal with this global threat. Bacteriophages (viruses that target bacteria) that kill ARB are one such alternative. While phages have been used clinically for decades with inconsistent results, a number of recent advances in phage selection, propagation and purification have enabled a reevaluation of their utility in contemporary clinical medicine. In most phage therapy cases, phages are administered in combination with antibiotics to ensure that patients receive the standard-of-care treatment. Some phages may work cooperatively with antibiotics to eradicate ARB, as often determined using non-standardized broth assays. We sought to develop a solid media-based assay to assess cooperativity between antibiotics and phages to offer a standardized platform for such testing. We modeled the interactions that occur between antibiotics and phages on solid medium to measure additive, antagonistic, and synergistic interactions. We then tested the method using different bacterial isolates, and identified a number of isolates where synergistic interactions were identified. These interactions were not dependent on the specific organism, phage family, or antibiotic used.A priorisusceptibility to the antibiotic or the specific phage were not requirements to observe synergistic interactions. Our data also confirm the potential for the restoration of vancomycin to treat Vancomycin Resistant Enterococcus (VRE) when used in combination with phages. Solid media assays for the detection of cooperative interactions between antibiotics and phages can be an accessible technique adopted by clinical laboratories to evaluate antibiotic and phage choices in phage therapy.
Efficient and multiplexed tracking of single cells using whole-body PET/CT
Authors: Nguyen Hieu T.M. , Das Neeladrisingha , Wang Yuting , Ruvalcaba Carlos , Mehadji Brahim , Roncali Emilie , Chan Charles K.F. , Pratx Guillem 
Published: August 2023

ABSTRACTIn vivomolecular imaging tools are crucially important for elucidating how cells move through complex biological systems, however, achieving single-cell sensitivity over the entire body remains challenging. Here, we report a highly sensitive and multiplexed approach for tracking upwards of 20 single cells simultaneously in the same subject using positron emission tomography (PET). The method relies on a new tracking algorithm (PEPT-EM) to push the cellular detection threshold to below 4 Bq/cell, and a streamlined workflow to reliably label single cells with over 50 Bq/cell of18F-fluorodeoxyglucose (FDG). To demonstrate the potential of method, we tracked the fate of over 70 melanoma cells after intracardiac injection and found they primarily arrested in the small capillaries of the pulmonary, musculoskeletal, and digestive organ systems. This study bolsters the evolving potential of PET in offering unmatched insights into the earliest phases of cell trafficking in physiological and pathological processes and in cell-based therapies.TEASERA novel PET imaging workflow reveals the fate of single cells across the body.
Nitric Oxide modulates spontaneous Ca2+release and ventricular arrhythmias during β-adrenergic signalling throughS-nitrosylation of Calcium/Calmodulin dependent kinase II
Authors: Power Amelia S. , Asamudo Esther , Worthington Luke P. I. , Alim Chidera C. , Parackal Raquel , Wallace Rachel S. , Ebenebe Obialunanma V. , Heller Brown Joan , Kohr Mark J. , Bers Donald M. , Erickson Jeffrey R. 
Published: August 2023

AbstractRationaleNitric oxide (NO) has been identified as a signalling molecule generated during β-adrenergic receptor (AR) stimulation in the heart. Furthermore, a role for NO in triggering spontaneous Ca2+release viaS-nitrosylation of Ca2+/calmodulin kinase II delta (CaMKIIδ) is emerging. NO donors are routinely used clinically for their cardioprotective effects in the heart, but it is unknown how NO donors modulate the pro-arrhythmic CaMKII to alter cardiac arrhythmia incidence.ObjectiveWe test the role ofS-nitrosylation of CaMKIIδ at the Cys-273 inhibitory site and Cys-290 activating site in cardiac Ca2+handling and arrhythmogenesis before and during β-AR stimulation.Methods and ResultsWe measured Ca2+-handling in isolated cardiomyocytes from C57BL/6J wild-type (WT) mice and mice lacking CaMKIIδ expression (CaMKIIδ-KO) or with deletion of theS-nitrosylation site on CaMKIIδ at Cys-273 or Cys-290 (CaMKIIδ-C273S and -C290A knock-in mice). Cardiomyocytes were exposed to NO donors, S-nitrosoglutathione (GSNO; 150 μM), sodium nitroprusside (SNP; 200 μM) and/or β-adrenergic agonist isoproterenol (ISO; 100 nM). WT and CaMKIIδ-KO cardiomyocytes treated with GSNO showed no change in Ca2+transient or spark properties under baseline conditions (0.5 Hz stimulation frequency). Both WT and CaMKIIδ-KO cardiomyocytes responded to ISO with a full inotropic and lusitropic Ca2+transient response as well as increased Ca2+spark frequency. However, the increase in Ca2+spark frequency was significantly attenuated in CaMKIIδ-KO cardiomyocytes. The protection from ISO-induced Ca2+sparks and waves was mimicked by GSNO pre-treatment in WT cardiomyocytes, but lost in CaMKIIδ-C273S cardiomyocytes that displayed a robust increase in Ca2+waves. This observation is consistent with CaMKIIδ-C273S-nitrosylation being critical in limiting ISO-induced arrhythmogenic sarcoplasmic reticulum Ca2+leak. When GSNO was applied after ISO this protection was not observed in WT or CaMKIIδ-C273S but was apparent in CaMKIIδ-C290A. In Langendorff-perfused isolated hearts, GSNO pre-treatment limited ISO-induced arrhythmias in WT but not CaMKIIδ-C273S hearts, while GSNO exposure after ISO sustained or exacerbated arrhythmic events.ConclusionsWe conclude that priorS-nitrosylation of CaMKIIδ at Cys-273 can limit subsequent β-AR induced arrhythmias, but thatS-nitrosylation at Cys-290 might worsen or sustain β-AR-induced arrhythmias. This has important implications for the administration of NO donors in the clinical setting.
Seroprevalence and molecular characterization of viral hepatitis and HIV co-infection in the Central African Republic
Authors: Basimane-Bisimwa Parvine , Koyaweda Giscard Wilfried , Ngaïganam Edgarthe , Vickos Ulrich , Sibiro Ornella Anne Demi , Yambiyo Brice Martial , Sombié Benjamin Seydou , Pélembi Pulchérie , Moussa Sandrine , Bekondi Claudine , Giles-Vernick Tamara , Manirakiza Alexandre , Vray Muriel , Komas Narcisse Patrice Joseph 
Published: August 2023

AbstractBackgroundThe Central African Republic (CAR) is one of the countries with the highest prevalence of viral hepatitis infection in the world. The present study describes the geographic distribution of viral hepatitis infections and molecular characterization of these viruses in the CAR.MethodologyOut of 12,599 persons enrolled during the 4th Multiple Indicator Cluster Survey of 2010 in the CAR, 10,621 Dried Blood Spot (DBS) samples were obtained and stored at -20°C. Of these DBS, 4,317 samples were randomly selected to represent all regions of the CAR. Serological tests for hepatitis B, D, and C viruses were performed using the ELISA technique. Molecular characterization was performed to identify strains.ResultsOf the 4,317 samples included, 53.2% were males and 46.8% females. The HBsAg prevalence among participants was 12.9% and that HBc-Ab was 19.7%. The overall prevalence of the HCV was 0.6%. Co-infection of HIV/HBV was 1.41% and that of HBV/HDV was 16.6%. A total of 77 HBV, 6 HIV, and 6 HDV isolates were successfully sequenced, with 72 HBV (93.5%) strains belonging to genotype E and 5 (6.5%) isolates belonging to genotype D. The 6 HDV isolates all belonged to clade 1, while 4 recombinants sub-type were identified among the 6 isolates of HIV.ConclusionOur study found a high prevalence of HBV, HBV/HDV and HBV/HIV co-infection, but a low prevalence of HCV. CAR is still in an area of high HBV endemicity. This study’s data and analyses would be useful for establishing an integrated viral hepatitis and HIV surveillance program in the CAR.
Serological surveillance reveals a high exposure to SARS-CoV-2 and altered immune response among COVID-19 unvaccinated Cameroonian individuals
Authors: Moguem Soubgui Arlette Flore , Ndeme Mboussi Wilfred Steve , Kojom Foko Loick Pradel , Embolo Enyegue Elisée Libert , Koanga Mogtomo Martin Luther 
Published: August 2023

AbstractBackgroundSurveillance of COVID-19/SARS-CoV-2 dynamics is crucial to understanding natural history and providing insights into the population’s exposure risk and specific susceptibilities. This study investigated the seroprevalence of SARS-CoV-2 antibodies, its predictors, and immunological status among unvaccinated patients in Cameroon.Materials and MethodsA multicentre cross-sectional study was conducted between January and September 2022 in the town of Douala. Patients were consecutively recruited, and data of interest were collected using a questionnaire. Blood samples were collected to determine Immunoglobin titres (IgM and IgG) by ALFA, CD4+ cells by flow cytometry, and interferon gamma (IFN-γ) and interleukin-6 (IL-6) by ELISA.ResultsA total of 342 patients aged 41.5 ± 13.9 years were included. Most participants (75.8%) were asymptomatic. The overall prevalence of IgM and IgG was 49.1% and 88.9%, respectively. Ageusia and anosmia have displayed the highest positive predictive values (90.9% and 82.4%) and specificity (98.9% and 98.3%). The predictors of IgM seropositivity were being aged 60 – 70 years (aOR = 0.54,p= 0.02) and ageusia (aOR = 9.31,p= 0.01), whereas those of IgG seropositivity included health facility (aOR = 0.23,p= 0.02) and ageusia (aOR = 0.21,p= 0.04). CD4+, IFN-γ, and IL-6 were impaired in seropositive individuals, with a confounding role of socio-demographic factors or comorbidities.ConclusionAlthough the WHO declared the end of COVID-19 as a public health emergency, the findings of this study indicate the need for continuous surveillance to adequately control the disease in Cameroon.
Modelling the Interplay between Responsive Individual Vaccination Decisions and the Spread of SARS-CoV-2
Authors: Wallrafen-Sam Karina , Quesada Maria Garcia , Lopman Benjamin A. , Jenness Samuel M. 
Published: August 2023

ABSTRACTThe uptake of COVID-19 vaccines remains low despite their high effectiveness. Epidemic models that represent decision-making psychology can provide insight into the potential impact of vaccine promotion interventions in the context of the COVID-19 pandemic. We coupled a network-based mathematical model of SARS-CoV-2 transmission in Georgia, USA with a social-psychological vaccination decision-making model in which vaccine side effects, post-vaccination infections, and other unidentified community-level factors could “nudge” individuals towards vaccine resistance while hospitalization spikes could nudge them towards willingness.Combining an increased probability of hospitalization-prompted resistant-to-willing switches with a decreased probability of willing-to-resistant switches prompted by unidentified community-level factors increased vaccine uptake and decreased SARS-CoV-2 incidence by as much as 30.7% and 24.0%, respectively. The latter probability had a greater impact than the former. This illustrates the disease prevention potential of vaccine promotion interventions that address community-level factors influencing decision-making and anticipate the case curve instead of reacting to it.
Comparison of SARS-CoV-2 variants of concern in primary human nasal cultures demonstrates Delta as most cytopathic and Omicron as fastest replicating
Authors: Tanneti Nikhila S , Patel Anant K , Tan Li Hui , Marques Andrew D , Perera Ranawaka A P M , Sherrill-Mix Scott , Kelly Brendan J , Renner David M , Collman Ronald G , Rodino Kyle , Lee Carole , Bushman Frederic D , Cohen Noam A , Weiss Susan R 
Published: August 2023

AbstractThe SARS-CoV-2 pandemic was marked with emerging viral variants, some of which were designated as variants of concern (VOCs) due to selection and rapid circulation in the human population. Here we elucidate functional features of each VOC linked to variations in replication rate. Patient-derived primary nasal cultures grown at air-liquid-interface (ALI) were used to model upper-respiratory infection and human lung epithelial cell lines used to model lower-respiratory infection. All VOCs replicated to higher titers than the ancestral virus, suggesting a selection for replication efficiency. In primary nasal cultures, Omicron replicated to the highest titers at early time points, followed by Delta, paralleling comparative studies of population sampling. All SARS-CoV-2 viruses entered the cell primarily via a transmembrane serine protease 2 (TMPRSS2)-dependent pathway, and Omicron was more likely to use an endosomal route of entry. All VOCs activated and overcame dsRNA-induced cellular responses including interferon (IFN) signaling, oligoadenylate ribonuclease L degradation and protein kinase R activation. Among the VOCs, Omicron infection induced expression of the most IFN and IFN stimulated genes. Infections in nasal cultures resulted in cellular damage, including a compromise of cell-barrier integrity and loss of nasal cilia and ciliary beating function, especially during Delta infection. Overall, Omicron was optimized for replication in the upper-respiratory system and least-favorable in the lower-respiratory cell line; and Delta was the most cytopathic for both upper and lower respiratory cells. Our findings highlight the functional differences among VOCs at the cellular level and imply distinct mechanisms of pathogenesis in infected individuals.ImportanceComparative analysis of infections by SARS-CoV-2 ancestral virus and variants of concern including Alpha, Beta, Delta, and Omicron, indicated that variants were selected for efficiency in replication. In infections of patient-derived primary nasal cultures grown at air-liquid-interface to model upper-respiratory infection, Omicron reached highest titers at early time points, a finding that was confirmed by parallel population sampling studies. While all infections overcame dsRNA-mediated host responses, infections with Omicron induced the strongest interferon and interferon stimulated gene response. In both primary nasal cultures and lower-respiratory cell line infections by Delta were most damaging to the cells as indicated by syncytia formation, loss of cell barrier integrity and nasal ciliary function.
Reorganization of Septin structures regulates early myogenesis
Authors: Ugorets Vladimir , Mendez Paul-Lennard , Zagrebin Dmitrii , Russo Giulia , Kerkhoff Yannic , Herpelinck Tim , Kotsaris Georgios , Jatzlau Jerome , Stricker Sigmar , Knaus Petra 
Published: August 2023

AbstractControlled myogenic differentiation is crucial for developmental formation, homeostatic maintenance and adult repair of skeletal muscle and relies on cell fate determinants in myogenic progenitors or resident stem cells. Proliferating muscle progenitors migrate, adopt spindle shape, align membranes and fuse into multinuclear syncytia. These processes are accompanied by cyto-architectural changes driven by rearranging of cytoskeletal components such as actin and microtubules. Here we highlight septins, the fourth component of the cytoskeleton, to represent an essential structural element of myoblasts. Specifically, Septin9 regulates myoblast differentiation during the early commitment process. Depletion of Septin9 in C2C12 cells and primary myoblasts led to a precocious switch from a proliferative towards a committed progenitor transcriptomic program. Additionally, we report Septin9 undergoing substantial reorganization and downregulation during myogenic differentiation. Together, we propose filamentous septin structures and their controlled reorganization in myoblasts to provide a key temporal regulation mechanism for the differentiation of myogenic progenitors.