bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for protein leverage on Total Energy Intake, but not Body Mass Index, in a large cohort of older adults
Authors: Honfo Sèwanou H. , Senior Alistair M. , Legault Véronique , Presse Nancy , Turcot Valérie , Gaudreau Pierrette , Simpson Stephen J. , Raubenheimer David , Cohen Alan A. 
Published: June 2023

AbstractBACKGROUNDProtein leverage (PL), the phenomenon of food consuming until absolute intake of protein meets a target value, regardless of shortfall or overconsuming for other nutrients in the diet and total energy intake (TEI). Evidence for PL was observed in humans, recently in a cohort of youth with obesity. This study aimed to test for PL and the protein leverage hypothesis (PLH) in a cohort of older adults.METHODSWe conducted a retrospective analysis of dietary intake in a cohort of 1699 community-dwelling older adults aged 67-84 years from the NuAge cohort. We computed TEI and the energy contribution (EC) from each macronutrient. The strength of leverage of macronutrients was assessed through power functions (TEI=µ * ECL). Body mass index (BMI) was calculated, and mixture models were fitted to predict TEI and BMI from macronutrient ECs.RESULTSThe mean TEI was 7,673 kJ and macronutrient ECs were 50.4 %, 33.2 % and 16.4 %, respectively for carbohydrates, fat, and protein. High carbohydrate intake was associated with low fat intake. There was a strong negative association (L= -0.37; p < 0.001) between the protein EC and TEI. Each percent of energy intake from protein reduced TEI by 77 kJ on average,ceteris paribus. BMI was unassociated with TEI in this cohort, so the PLH could not be tested here.CONCLUSIONSFindings indicate clear evidence for PL on TEI, but not on BMI, likely because TEI and BMI become increasingly uncoupled during aging.
Prognostic Impact of Preoperative Atrial Fibrillation in Patients Undergoing Heart Surgery in Cardiogenic Shock
Authors: Kowalewski Mariusz , Raffa Giuseppe M. , Pasierski Michał , Pasierski Michał , Kołodziejczak Michalina , Litwinowicz Radosław , Wańha Wojciech , Wojakowski Wojciech , Rogowski Jan , Jasiński Marek , Widenka Kazimierz , Hirnle Tomasz , Deja Marek , Bartus Krzysztof , Lorusso Roberto , Tobota Zdzisław , Maruszewski Bohdan , Suwalski Piotr 
Published: June 2023

AbstractBackgroundSurgical intervention in the setting of cardiogenic shock (CS) is burdened with high mortality. Due to acute condition, detailed diagnoses and risk assessment is often precluded. Atrial fibrillation (AF) is a risk factor for perioperative complications and worse survival but little is known about AF patients operated in CS. Current analysis aimed to determine prognostic impact of preoperative AF in patients undergoing heart surgery in CS.MethodsWe analyzed data from the Polish National Registry of Cardiac Surgery (KROK) Procedures. Between 2012 and 2021, 4,852 patients presented with CS and were referred for cardiac surgery in 37 centers. Total of 624 (13%) patients had AF history. Cox proportional hazards models were used for computations. Propensity score (nearest neighbor) matching for the comparison of patients with and without AF was performed.ResultsMedian follow-up was 4.6 years (max.10.0), mean age was 62 (±15) years and 68% patients were men. Thirty-day mortality was 36%. The origin of CS included acute myocardial infarction (36%), acute aortic dissection (22%) and valvular dysfunction (13%). In an unadjusted analysis, patients with underlying AF had almost 20% higher mortality risk (HR 1.19, 95% CIs 1.06-1.34; P=0.004). Propensity score matching returned 597 pairs with similar baseline characteristics; AF remained a significant prognostic factor for worse survival (HR 1.19, 95% CI 1.00-1.40; P=0.045).ConclusionsAmong patients with CS referred for cardiac surgery, history of AF was a significant risk factor for mortality. Role of concomitant AF ablation and/or left atrial appendage occlusion should be addressed in the future.
High rates of SARS-CoV-2 infection in pregnant Ugandan women and association with stunting in infancy
Authors: Jacobson Karen B. , Röltgen Katharina , Lam Brandon , Nayebare Patience , Kakuru Abel , Kizza Jimmy , Aguti Miriam , Nankya Felistas , Briggs Jessica , Takahashi Saki , Greenhouse Bryan , Rodriguez-Barraquer Isabel , Ploeg Kattria van der , Wohlstadter Jacob N. , Sigal George B. , Roh Michelle E , Nankabirwa Joaniter I. , Cuu Gloria , Gaw Stephanie L. , Rosenthal Philip J. , Kamya Moses R. , Ssewanyana Isaac , Dorsey Grant , Boyd Scott D. , Jagannathan Prasanna 
Published: June 2023

AbstractBackgroundSARS-CoV-2 has been well studied in resource-rich areas but many questions remain about effects of infection in African populations, particularly in vulnerable groups such as pregnant women.MethodsWe describe SARS-CoV-2 immunoglobulin (Ig) G and IgM antibody responses and clinical outcomes in mother-infant dyads enrolled in malaria chemoprevention trials in Uganda.ResultsFrom December 2020 to February 2022, among 400 unvaccinated pregnant women, serologic assessments revealed that 128 (32%) were seronegative for anti-SARS-CoV-2 IgG and IgM at enrollment and delivery, 80 (20%) were infected either prior to or early in pregnancy, and 192 (48%) were infected or re-infected with SARS-CoV-2 during pregnancy. We observed preferential binding of plasma IgG to Wuhan-Hu-1-like antigens in individuals seroconverting up to early 2021, and to Delta variant antigens in a subset of individuals in mid-2021. Breadth of IgG binding to all variants improved over time. No participants experienced severe respiratory illness during the study. SARS-CoV-2 infection in early pregnancy was associated with lower median length-for-age Z-score at age 3 months compared with no infection or late pregnancy infection (- 1.54 versus −0.37 and −0.51, p=0.009).ConclusionPregnant Ugandan women experienced high levels of SARS-CoV-2 infection without severe respiratory illness. Variant-specific serology testing demonstrated evidence of antibody affinity maturation at the population level. Early gestational SARS-CoV-2 infection was associated with shorter stature in early infancy.FundingThis work was supported by: Stanford MCHRI/Stephen Bechtel Endowed Fellowship in Pediatric Translational Medicine (KJ), Swiss National Science Foundation PRIMA grant PR00P3_208580 (KR), the Bill and Melinda Gates Foundation, and NIAID (T32-AI052073, U01- AI141308, U01-AI155325).
The Benchtop mesoSPIM: a next-generation open-source light-sheet microscope for large cleared samples
Authors: Vladimirov Nikita , Voigt Fabian F. , Naert Thomas , Araujo Gabriela R. , Cai Ruiyao , Reuss Anna Maria , Zhao Shan , Schmid Patricia , Hildebrand Sven , Schaettin Martina , Groos Dominik , Mateos José María , Bethge Philipp , Yamamoto Taiyo , Aerne Valentino , Roebroeck Alard , Ertürk Ali , Aguzzi Adriano , Ziegler Urs , Stoeckli Esther , Baudis Laura , Lienkamp Soeren S. , Helmchen Fritjof 
Published: June 2023

AbstractIn 2015, we launched the mesoSPIM initiative (www.mesospim.org), an open-source project for making light-sheet microscopy of large cleared tissues more accessible. Meanwhile, the demand for imaging larger samples at higher speed and resolution has increased, requiring major improvements in the capabilities of light-sheet microscopy. Here, we introduce the next-generation mesoSPIM (“Benchtop”) with significantly increased field of view, improved resolution, higher throughput, more affordable cost and simpler assembly compared to the original version. We developed a new method for testing objectives, enabling us to select detection objectives optimal for light-sheet imaging with large-sensor sCMOS cameras. The new mesoSPIM achieves high spatial resolution (1.5 µm laterally, 3.3 µm axially) across the entire field of view, a magnification up to 20x, and supports sample sizes ranging from sub-mm up to several centimetres, while being compatible with multiple clearing techniques. The new microscope serves a broad range of applications in neuroscience, developmental biology, and even physics.
Comparison of Transcatheter Edge-to-Edge Mitral Valve Repair for Primary Mitral Regurgitation Outcomes to Hospital Volumes of Surgical Mitral Valve Repair
Authors: Grayburn Paul A. , Mack Michael J. , Manandhar Pratik , Kosinski Andrzej S. , Sannino Anna , Smith Robert L. , Szerlip Molly , Vemulapalli Sreekanth 
Published: June 2023

ABSTRACTBackgroundTranscatheter edge-to-edge mitral valve (MV) repair (TEER) is an effective treatment for patients with primary mitral regurgitation (MR) at prohibitive risk for surgical MV repair (MVr). High volume MVr centers and high volume TEER centers have better outcomes than low volume centers, respectively. However little is known about whether MVr volume, and specifically complex MVr volume, predicts TEER outcomes. We hypothesized that high volume MV surgical centers would have superior risk-adjusted outcomes for TEER than tlow volume centers.MethodsWe combined data from the ACC/STS TVT registry and the STS adult cardiac surgery database. Complex MVr, defined as leaflet resection or artificial chords with or without annuloplasty was evaluated as a continuous variable and as pre-defined categories (<25, 25-49 and ≥ 50 MV repairs/year). A generalized linear mixed model was used to evaluate risk-adjusted in-hospital/30-day mortality, 30 day HF readmission and TEER success (MR ≤ 2+ and gradient < 5 mmHg).ResultsThe study comprised 41,834 patients from 500 sites. TEER mortality at 30-days was 3.5% with no significant difference across MVr volume on unadjusted (p=0.141) or adjusted (p=0.071) analysis of volume as a continuous variable. One-year mortality was 15.0% and was lower for higher MVr volume centers when adjusted for clinical and demographic variables (p=0.027). HF readmission at one year was 9.4% and was statistically significantly lower in high volume centers on both unadjusted (p=0.017) or adjusted (p-0.015) analysis. TEER success was 54.6% and was not statistically significantly different across MV surgical site volumes (p=0.4271).ConclusionsTEER can be safely performed in centers with low volumes of complex MV repair. However, one-year mortality and HF readmission are superior at centers with higher MVr volume.
Click-Based Determination of Accumulation of Molecules inEscherichia coli
Authors: Ongwae George M. , Liu Zichen , Feng Shasha , Chordia Mahendra D. , Sharifian Gh. Mohammad , Dash Rachita , Dalesandro Brianna E. , Guo Taijie , Sharpless Karl Barry , Dong Jiajia , Siegrist M. Sloan , Im Wonpil , Pires Marcos M. 
Published: June 2023

ABSTRACTGram-negative bacterial pathogens pose a significant challenge in drug development due to their outer membranes, which impede the permeation of small molecules. The lack of widely adoptable methods to measure the cytosolic accumulation of compounds in bacterial cells has hindered drug discovery efforts. To address this challenge, we developed the CHloroalkane Azide Membrane Permeability (CHAMP) assay, specifically designed to assess molecule accumulation in the cytosol of Gram-negative bacteria. The CHAMP analysis utilizes biorthogonal epitopes anchored within HaloTag-expressing bacteria and measures the cytosolic arrival of azide-bearing test molecules through strain-promoted azide-alkyne cycloaddition. This workflow allows for robust and rapid accumulation measurements of thousands of azide-tagged small molecules. Our approach consistently yields a large number of accumulation profiles, significantly exceeding the scale of previous measurements inEscherichia coli(E. coli). We have validated the CHAMP assay across various chemical and biological contexts, including hyperporinated cells, membrane-permeabilized cells, and E. coli strains with impaired TolC function, a key component of the efflux pump. The CHAMP platform provides a simple, high-throughput, and accessible method that enables the analysis of over 1,000 molecules within hours. This technique addresses a critical gap in antimicrobial research, potentially accelerating the development of effective agents against Gram-negative pathogens.
Cell arrangement impacts metabolic activity and antibiotic tolerance inPseudomonas aeruginosabiofilms
Authors: Dayton Hannah , Kiss Julie , Wei Mian , Chauhan Shradha , LaMarre Emily , Cornell William Cole , Morgan Chase J. , Janakiraman Anuradha , Min Wei , Tomer Raju , Price-Whelan Alexa , Nirody Jasmine A , Dietrich Lars E.P. 
Published: June 2023

ABSTRACTCells must access resources to survive, and the anatomy of multicellular structures influences this access. In diverse multicellular eukaryotes, resources are provided by internal conduits that allow substances to travel more readily through tissue than they would via diffusion. Microbes growing in multicellular structures, called biofilms, are also affected by differential access to resources and we hypothesized that this is influenced by the physical arrangement of the cells. In this study, we examined the microanatomy of biofilms formed by the pathogenic bacteriumPseudomonas aeruginosaand discovered that clonal cells form striations that are packed lengthwise across most of a mature biofilm’s depth. We identified mutants, including those defective in pilus function and in O-antigen attachment, that show alterations to this lengthwise packing phenotype. Consistent with the notion that cellular arrangement affects access to resources within the biofilm, we found that while the wild type shows even distribution of tested substrates across depth, the mutants show accumulation of substrates at the biofilm boundaries. Furthermore, we found that altered cellular arrangement within biofilms affects the localization of metabolic activity, the survival of resident cells, and the susceptibility of subpopulations to antibiotic treatment. Our observations provide insight into cellular features that determine biofilm microanatomy, with consequences for physiological differentiation and drug sensitivity.
Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1
Authors: Smith Brandon C. , Tinkey Rachel A. , Mariam Arshiya , Habean Maria L. , Dutta Ranjan , Williams Jessica L. 
Published: June 2023

AbstractMultiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS). Infiltrating inflammatory immune cells perpetuate demyelination and axonal damage in the CNS and significantly contribute to pathology and clinical deficits. While the cytokine interferon (IFN)γ is classically described as deleterious in acute CNS autoimmunity, we and others have shown astrocytic IFNγ signaling also has a neuroprotective role. Here, we performed RNA sequencing and ingenuity pathway analysis on IFNγ-treated astrocytes and found that PD-L1 was prominently expressed. Using a PD-1/PD-L1 antagonist, we determined that apoptosis was reduced in leukocytes exposed to IFNγ-treated astrocytesin vitro. To further elucidate the role of astrocytic IFNγ signaling on the PD-1/PD-L1 axisin vivo, we induced the experimental autoimmune encephalomyelitis (EAE) model of MS inAldh1l1-CreERT2,Ifngr1fl/flmice. Mice with conditional astrocytic deletion of IFNγ receptor exhibited a reduction in PD-L1 expression which corresponded to increased infiltrating leukocytes, particularly from the myeloid lineage, and exacerbated clinical disease. PD-1 agonism reduced EAE severity and CNS-infiltrating leukocytes. Importantly, PD-1 is expressed by myeloid cells surrounding MS lesions. These data support that IFNγ signaling in astrocytes diminishes inflammation during chronic autoimmunity via upregulation of PD-L1, suggesting potential therapeutic benefit for MS patients.
N-terminal targeting sequences and coding sequences act in concert to determine the localization and trafficking pathway of apicoplast proteins inToxoplasma gondii
Authors: Anjum Sofia , Prasad Aparna , Mastud Pragati , Patankar Swati 
Published: June 2023

AbstractToxoplasma gondiihas a relict plastid, the apicoplast, to which proteins are targeted after synthesis in the cytosol. Proteins exclusively found in the apicoplast use a Golgi-independent route for trafficking, while dually targeted proteins found in both the apicoplast and the mitochondrion use a Golgi-dependent route. For apicoplast targeting, N-terminal signal sequences have been shown to direct the localization of different reporters. In this study, we use chimeric proteins to dissect out the roles of N-terminal sequences and coding sequences in apicoplast localization and the choice of the trafficking route. We show that when the N-termini of a dually targeted protein,TgTPx1/2, or of an apicoplast protein,TgACP, are fused with the reporter protein, enhanced Green Fluorescent Protein (eGFP) or endogenous proteins,TgSOD2,TgSOD3,TgACP orTgTPx1/2, the chimeric proteins exhibit flexibility in apicoplast targeting depending on the coding sequences. Further, the chimeras that are localized to the apicoplast use different trafficking pathways depending on the combination of the N-terminal signals and the coding sequences. This report shows, for the first time, that in addition to the N-terminal signal sequences, targeting and trafficking signals also reside within the coding sequences of apicoplast proteins.
Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis
Authors: Mancini Fabrizio E. , Humphreys Paul E.A. , Woods Steven , Bates Nicola , Cuvertino Sara , O’Flaherty Julieta , Biant Leela , Domingos Marco A.N. , Kimber Susan J. 
Published: June 2023

AbstractOsteoarthritis is the most common degenerative joint condition, leading to articular cartilage (AC) degradation, chronic pain and immobility. The lack of appropriate therapies that provide tissue restoration combined with the limited lifespan of joint-replacement implants indicate the need for alternative AC regeneration strategies. Differentiation of human pluripotent stem cells (hPSCs) into AC progenitors may provide a long-term regenerative solution but are still limited due to the continued reliance upon growth factors to recapitulate developmental signalling processes. Recently, TTNPB, a small molecule activator of retinoic acid receptors (RARs), has been shown to be sufficient to guide mesodermal specification and early chondrogenesis of hPSCs. Here, we modified our previous differentiation protocol, by supplementing cells with TTNPB and administering BMP2 at specific times to enhance early development. Transcriptomic analyses indicated that activation of RAR signalling significantly upregulated genes related to limb and embryonic skeletal development in the early stages of the protocol and upregulated genes related to AC development in later stages. Chondroprogenitors obtained from RAPID-E could generate cartilaginous pellets that expressed AC-related matrix proteins such as Lubricin, Aggrecan, and Collagen II. This protocol could lay the foundations for cell therapy strategies for osteoarthritis and improve the understanding of AC development in humans.
Drug Resistance without a cost? Common and uncommon routes to fosfomycin resistance in UropathogenicEscherichia coli
Authors: Bermudez Tomas A. , Brannon John R. , Dudipala Neha , Reasoner Seth , Morales Grace , Wiebe Michelle , Cecala Mia , Beebout Connor , Amir Omar , Hadjifrangiskou Maria 
Published: June 2023

ABSTRACTFosfomycin kills bacteria by blocking the binding of phosphoenolpyruvate (PEP) to the bacterial enzyme MurA and halting peptidoglycan synthesis. While its use has increased with the emergence of antibiotic resistance, the mechanisms leading to fosfomycin resistance remain relatively unexplored. In uropathogenicEscherichia coli(UPEC) that accounts for >75% of urinary tract infections (UTIs), fosfomycin enters the cell primarily through UhpT, which transports glucose-6-phosphate (G6P) glycolysis intermediate into the cell. Mutations inuhpT lead to fosfomycin resistance and have been identified during antimicrobial susceptibility testing (AST) in non-susceptible inner colonies that form within the zone of inhibition. However, EUCAST and CLSI guidelines differ in how to read fosfomycin AST when such resistant colonies arise. Work from our lab and others demonstrated that glycolysis is dispensable during acute UTI. Moreover, G6P is scarce in urine, prompting us to test the hypothesis thatuhpmutations may not impart a fitness cost to the pathogen. We report that loss ofuhpindeed does not impair UPEC pathogenesis and that clinical isolates exist that lack theuhplocus altogether. Analysis of non-susceptible inner colonies revealed a suite of novel genes involved in fosfomycin resistance. One of them is PykF that converts PEP to pyruvate during glycolysis. Single deletions ofpykFor its anaerobic homologpykAdo not attenuate UPEC. Based on our data, we raise the alarm that multiple routes lead to fosfomycin resistance and do not affect pathogenesis and propose that the current EUCAST and CLSI guidelines unify into how they evaluate fosfomycin AST.IMPORTANCEWhile fosfomycin resistance is rare, the observation of non-susceptible subpopulations among clinicalEscherichia coliisolates is a common phenomenon during antimicrobial susceptibility testing (AST) in American and European clinical labs. Previous evidence suggests that mutations eliciting this phenotype are of high biological cost to the pathogen during infection, leading to current recommendations of neglecting non-susceptible colonies during AST. Here we report that the most common route to fosfomycin resistance, as well as novel routes described in this work do not impair virulence in uropathogenicE. coli, the major cause of urinary tract infections, suggesting a re-evaluation of current susceptibility guidelines is warranted.