bluuebunny/crossref_metadata_2025_split huggingface dataset:
Xenografts Show Signs of Concentric Hypertrophy and Dynamic Left Ventricular Outflow Tract Obstruction After Orthotopic Pig-to-baboon Heart Transplantation
Authors: Längin Matthias , Buttgereit Ines , Reichart Bruno , Panelli Alessandro , Radan Julia , Mokelke Maren , Neumann Elisabeth , Bender Martin , Michel Sebastian , Ellgass Reinhard , Ying Jiawei , Fresch Ann Kathrin , Mayr Tanja , Steen Stig , Paskevicius Audrius , Egerer Stefanie , Bähr Andrea , Kessler Barbara , Klymiuk Nikolai , Binder Uli , Skerra Arne , Ledderose Stephan , Müller Susanna , Walz Christoph , Hagl Christian , Wolf Eckhard , Ayares David , Brenner Paolo , Abicht Jan-Michael 
Published: August 2023

Background.
Orthotopic cardiac xenotransplantation has seen substantial advancement in the last years and the initiation of a clinical pilot study is close. However, donor organ overgrowth has been a major hurdle for preclinical experiments, resulting in loss of function and the decease of the recipient. A better understanding of the pathogenesis of organ overgrowth after xenotransplantation is necessary before clinical application.

Methods.
Hearts from genetically modified (GGTA1-KO, hCD46/hTBM transgenic) juvenile pigs were orthotopically transplanted into male baboons. Group I (control, n = 3) received immunosuppression based on costimulation blockade, group II (growth inhibition, n = 9) was additionally treated with mechanistic target of rapamycin inhibitor, antihypertensive medication, and fast corticoid tapering. Thyroid hormones and insulin-like growth factor 1 were measured before transplantation and before euthanasia, left ventricular (LV) growth was assessed by echocardiography, and hemodynamic data were recorded via a wireless implant.

Results.
Insulin-like growth factor 1 was higher in baboons than in donor piglets but dropped to porcine levels at the end of the experiments in group I. LV mass increase was 10-fold faster in group I than in group II. This increase was caused by nonphysiological LV wall enlargement. Additionally, pressure gradients between LV and the ascending aorta developed, and signs of dynamic left ventricular outflow tract (LVOT) obstruction appeared.

Conclusions.
After orthotopic xenotransplantation in baboon recipients, untreated porcine hearts showed rapidly progressing concentric hypertrophy with dynamic LVOT obstruction, mimicking hypertrophic obstructive cardiomyopathy in humans. Antihypertensive and antiproliferative drugs reduced growth rate and inhibited LVOT obstruction, thereby preventing loss of function.
Delayed Graft Function Among Kidney Transplant Recipients Is Associated With an Increased Risk of Urinary Tract Infection and BK Viremia
Authors: Alshaikh Eman A. , Astor Brad C. , Muth Brenda , Jorgenson Margaret , Swanson Kurt , Garg Neetika , Aziz Fahad , Mohamed Maha , Mandelbrot Didier , Parajuli Sandesh 
Published: August 2023

Background.
Delayed graft function (DGF) among deceased donor kidney transplant recipients (DDKTRs) is a well-known risk factor for allograft rejection, decreased graft survival, and increased cost. Although DGF is associated with an increased risk of rejection, it is unclear whether it also increases the risk of infection.

Methods.
We reviewed all adult DDKTRs at our center between 2010 and 2018. The primary outcomes of interest were BK viremia, cytomegalovirus viremia, pneumonia, and urinary tract infection (UTI) within the first year of transplant. Additional analysis was made with censoring follow-up at the time of allograft rejection.

Results.
A total of 1512 DDKTRs were included, of whom 468 (31%) had DGF. As expected, several recipient, donor, and baseline immunological characteristics differed by DGF status. After adjustment, DGF was significantly associated with an increased risk of BK viremia (hazard ratio: 1.34; 95% confidence interval, 1.0-1.81; P = 0.049) and UTI (hazard ratio: 1.70; 95% confidence interval, 1.31-2.19; P < 0.001) but not cytomegalovirus viremia or pneumonia. Associations were similar in models censored at the time of rejection.

Conclusions.
DGF is associated with an increased risk of early infectious complications, mainly UTI and BK viremia. Close monitoring and appropriate management are warranted for better outcomes in this unique population.
YOKENELLA REGENSBURGEI URINARY TRACT INFECTION IN AN IMMUNOCOMPETENT PATIENT: A CASE REPORT
Authors: V Annie Sheeba , Suji Thangamani , Jayanth Selvin Theodore , Sahni Rani Diana 
Published: August 2023

Yokenella regensburgei, belonging to the order Enterobacterales, is a rare and emerging human pathogen reported to cause both superficial and invasive infections. The 13 case reports in literature worldwide highlight blood, bone and wound infections. To our knowledge this is the first case description of Yokenella regensburgei causing UTI in a 69-year old immunocompetent patient which was isolated in 2 separate specimens and identified using MALDI-TOF MS (bioMérieux, Version 3.2, France). It was found to be susceptible to most antimicrobials but resistant to penicillin, amoxicillin-clavulanate, cefoxitin, colistin. Inducible chromosomal ampC resistance was demonstrated on disk approximation test and blaYOC-1 Class C beta-lactamase, beta lactamase superfamily and MBL fold metallo-hydrolase genes were found on whole genome sequencing.
Gain-of-function MARK4 variant associates with pediatric neurodevelopmental disorder and dysmorphism
Authors: Samra Simran , Sharma Mehul , Vaseghi-Shanjani Maryam , Del Bel Kate L. , Byres Loryn , Lin Susan , Dalmann Joshua , Salman Areesha , Mwenifumbo Jill , Modi Bhavi P. , Biggs Catherine M. , Boelman Cyrus , Clarke Lorne A. , Lehman Anna , Turvey Stuart E. 
Published: August 2023

AbstractMicrotubule affinity regulating kinase 4 (MARK4) is a serine/threonine kinase that plays a key role in tau phosphorylation and regulation of the mTOR pathway. Abnormal tau phosphorylation and dysregulation of the mTOR pathway are implicated in neurodegenerative and neurodevelopmental disorders.Here, we report a novel gain-of-function variant inMARK4in two siblings with childhood-onset neurodevelopmental disability and dysmorphic features.The siblings carry a germline heterozygous missenseMARK4variant c.604T>C; p.Phe202Leu, located in the catalytic domain of the kinase, which they inherited from their unaffected, somatic mosaic mother. Functional studies show that this amino acid substitution has no impact on protein expression but instead increases the ability of MARK4 to phosphorylate tau isoforms found in the fetal and adult brain. TheMARK4variant also increases phosphorylation of ribosomal protein S6, indicating upregulation of the mTORC1 pathway.This is the first study to link a germline monoallelicMARK4variant to a childhood-onset neurodevelopmental disorder characterized by global developmental delay, intellectual disability, behavioral abnormalities, and dysmorphic features.
Interrogating basal ganglia circuit function in Parkinson’s disease and dystonia
Authors: Sumarac S , Spencer KA , Steiner LA , Fearon C , Haniff E , Kühn AA , Hodaie M , Kalia SK , Lozano AM , Fasano A , Hutchison WD , Milosevic L 
Published: August 2023

AbstractBackgroundThe dichotomy between the hypo-versus hyperkinetic nature of Parkinson’s disease (PD) and dystonia, respectively, is thought to be reflected in the underlying basal ganglia pathophysiology.ObjectiveInvestigate differences in globus pallidus internus (GPi) neuronal activity, and short- and long-term plasticity of direct pathway projections.ResultsGPi neurons were slower, burstier, and less regular in dystonia. In PD, symptom severity positively correlated with the power of low-beta frequency spiketrain oscillations. In dystonia, symptom severity negatively correlated with firing rate, and positively correlated with neuronal variability and the power of theta frequency spiketrain oscillations. Dystonia was moreover associated with less long-term plasticity and slower synaptic depression.ConclusionWe substantiated claims of hyper-versus hypofunctional GPi output in PD versus dystonia, and provided cellular-level validation of the pathological nature of theta and low-beta oscillations in respective disorders. Such circuit changes may be underlain by disease-related differences in plasticity of striato-pallidal synapses.
Bushfire alters the gut microbiome in endangered Kangaroo Island echidnas (Tachyglossus aculeatus multiaculeatus)
Authors: Perry Tahlia , Lu Amy , McKelvey Michael W. , Rismiller Peggy D. , Grützner Frank 
Published: August 2023

AbstractKangaroo Island experienced extensive bushfires in December 2019 and January 2020, affecting almost half of the island. This impacted several threatened species including the Kangaroo Island echidnas (Tachyglossus aculeatus multiaculeatus). Echidnas can often survive fires, however, changes in soil chemistry and food availability raises questions about the impact on echidna gut health and foraging behaviours. Due to local participation in the citizen science project, EchidnaCSI, echidna scats were collected before and after the fires to directly assess how fire affects their gut microbiomes. Metabarcoding of scat microbiota (n = 13) revealed substantial changes in bacterial composition of echidna faeces post-bushfire when compared to samples collected prior to bushfires. Before the fires, echidna gut microbiomes were more variable and contained mostly soil-associated bacteria, whereas post-fire samples shifted to uniform bacterial communities consisting of lactic acid and gut commensal bacteria. Interestingly, changes were observed in scats collected in both burnt and unburnt regions of the island, suggesting echidnas are foraging between these areas. This is the first study to document changes in gut microbiome of any mammal following bushfires. More work is needed to investigate if the gut bacterial communities continue to change as areas recover from fires.
Neural computation in the brainstem for visceral sensation-driven haemodynamics
Authors: Lee Jiho , Mun Junseung , Park Sung-Min 
Published: August 2023

AbstractThe brainstem serves as an intermediary processor of haemodynamic sensations via nucleus tractus solitaries (NTS) in regulating circulatory system. After sensing visceral inputs, the NTS relays information to efferent pathways to modulate peripheral viscera. However, the neural computation mechanism underlying how the NTS processes viscerosensory input remains unknown. Here, we show the computational principles embedded inside the NTS of rats, producing haemodynamic modulation in concert. Our findings demonstrate that the collective dynamics leveraging from neuronal population within the NTS neural circuit encode input-driven haemodynamics. The NTS exhibits the neural trajectory, the dynamical trace of neural states, which is confined to low-dimensional latent space and may represent haemodynamic perturbations. Surprisingly, by normalizing neural trajectory of rats, we found the across-rat common rules for the viscerosensory-information processing by the NTS. Furthermore, the common rules allowed to identify inter-subject variable haemodynamics by quantifying the computational mechanisms in neuro-haemodynamic axis. Our findings provide pioneering insights into understanding the neural computation involved in regulation of visceral functions by the autonomic nervous system.
CLOCK Mediates Delay in Cardiac Myofibroblast Formation and Attenuates Progression of Myocardial Fibrosis through Inhibition of Smad 3 Transcriptional Activity
Authors: Zhou Yongqiao , Liao Minqi , Chen Lihua , Yao Yongzhao , Huang Zhichao , Yang Yanhua , Su Shaohui , Liang Guangzhu , Wu Zhihao , Ouyang Shumin , Guo Suxia 
Published: August 2023

AbstractIntroductionMyocardial fibrosis, characterized by excessive extracellular matrix deposition, leading to adverse cardiac remodeling and impaired function. The differentiation of cardiac fibroblasts into myofibroblasts plays a pivotal role in this process. The involvement of the core clock protein CLOCK in the formation of cardiac myofibroblasts and the advancement of myocardial fibrosis is not well understood. This study aims to investigate how CLOCK modulates cardiac myofibroblast differentiation and attenuates myocardial fibrosis by inhibiting Smad3 transcriptional activity.MethodsIn vivo, adeno-associated virus 9 was utilized for overexpression or silencing of the CLOCK gene via mice intravenous injection. In vitro experiments were conducted using primary cultures of cardiac fibroblasts isolated from mouse hearts to examine the expression levels of molecular markers associated with myofibroblast differentiation, such as α-smooth muscle actin (α-SMA) and collagen I. Additionally, a Smad3 luciferase reporter gene experiment was employed to assess the transcriptional activity of Smad3 under CLOCK regulation.ResultsThe results demonstrate that CLOCK overexpression significantly reduces the expression of α-SMA and collagen I in cardiac fibroblasts, indicating a suppression of myofibroblast formation. Conversely, CLOCK knockdown enhances the expression of these fibrotic markers. Interestingly, CLOCK was found to negatively regulate the transcriptional activity of Smad3, suggesting a potential mechanism by which CLOCK exerts its inhibitory effect on cardiac fibrosis. Specifically, CLOCK interacts with Smad3, inhibiting its nuclear translocation and subsequent activation of fibro genic gene expression.ConclusionThese findings highlight the crucial role of CLOCK in the regulation of cardiac myofibroblast formation and the progression of myocardial fibrosis. CLOCK appears to exert an inhibitory effect on fibrotic signaling pathways, partially through the inhibition of Smad3 transcriptional activity. This study provides novel insights into the molecular mechanisms underlying cardiac fibrosis and emphasizes the therapeutic potential of targeting CLOCK-mediated pathways for treating myocardial fibrosis.
Wastewater-based surveillance is an efficient monitoring tool for tracking influenza A virus in the community
Authors: Kirsi-Maarit Lehto , Rafiqul Hyder , Annika Länsivaara , Oskari Luomala , Anssi Lipponen , Hokajärvi Anna-Maria , Annamari Heikinheimo , Tarja Pitkänen , Sami Oikarinen ,   WastPan Study Group
Published: August 2023

AbstractAround the world, influenza A virus has caused severe pandemics, and the risk of future pandemics remains high. Currently, influenza A virus surveillance is based on the clinical diagnosis and reporting of disease cases. In this study, we apply wastewater-based surveillance to monitor the incidence of the influenza A virus at the population level. We report incidence data of the influenza A virus in 10 wastewater treatment plant catchment areas covering 40% of the Finnish population. Altogether, 141 monthly composite influent wastewater samples (collected between April 2020 and May 2021) were analysed from supernatant fraction using influenza A virus specific RT-qPCR method. During the study period, an influenza A virus epidemic occurred in two waves in Finland. This study shows that the influenza A virus can be detected from the supernatant fraction of 24 h composite influent wastewater samples. The influenza A virus gene copy number in wastewater correlated with the number of confirmed disease cases in the Finnish National Infectious Diseases Register. The Kendall’s τ correlation strength was over 0.600 in all wastewater treatment plants, save for one, which was 0.459. The strongest correlations were 0.761 and 0.833. Wastewater-based surveillance of the influenza A virus is an unbiased method and cost-efficiently reflects the circulation of the virus in the entire population. Thus, wastewater monitoring complements the available, but often too sparse, information from individual testing and improves health care and public health preparedness for influenza A virus pandemics.
Uncoupling interferons and the interferon signature explain clinical and transcriptional subsets in SLE
Authors: Gómez-Bañuelos Eduardo , Goldman Daniel W. , Andrade Victoria , Darrah Erika , Petri Michelle , Andrade Felipe 
Published: August 2023

SummaryInterferons (IFN) are thought to be key players in systemic lupus erythematosus (SLE). The unique and interactive roles of the different IFN families in SLE pathogenesis, however, remain poorly understood. Using reporter cells engineered to precisely quantify IFN-I, IFN-II and IFN-III activity levels in serum/plasma, we found that while IFNs play essential role in SLE pathogenesis and disease activity, they are only significant in specific subsets of patients. Interestingly, whereas IFN-I is the main IFN that governs disease activity in SLE, clinical subsets are defined by the co-elevation of IFN-II and IFN-III. Thus, increased IFN-I alone was only associated with cutaneous lupus. In contrast, systemic features, such as nephritis, were linked to co-elevation of IFN-I plus IFN-II and IFN-III, implying a synergistic effect of IFNs in severe SLE. Intriguingly, while increased IFN-I levels were strongly associated with IFN-induced gene expression (93.5%), in up to 64% of cases, the IFN signature was not associated with IFN-I. Importantly, neither IFN-II nor IFN-III explained IFN-induced gene expression in patients with normal IFN-I levels, and not every feature in SLE was associated with elevated IFNs, suggesting IFN-independent subsets in SLE. Together, the data suggest that, unlike the IFN signature, direct quantification of bioactive IFNs can identify pathogenic and clinically relevant SLE subsets amenable for precise anti-IFN therapies. Since IFN-I is only elevated in a subset of SLE patients expressing the IFN signature, this study explains the heterogeneous response in clinical trials targeting IFN-I, where patients were selected based on IFN-induced gene expression rather than IFN-I levels.
Antimicrobial efficacy ofin-situplasma-generated ozone againstPseudomonas aeruginosabiofilms in drains and water-submerged surfaces
Authors: Pajak-Zajac Malgorzata Z. , Dowdell Adam , Buckley Anthony , Potts Hugh E. , Smith Andrew , Diver Declan A. 
Published: August 2023

AbstractAimsTo demonstrate a novel method of gaseous disinfection that can eradicate biofilms inhabiting elusive regions of plumbing systems.Methods & ResultsHighly biocidal ozone is generatedin-situusing the ambient air inside a model sink and drain, via portable plasma discharge, with the plasma device sealing the treated area, ensuring no ozone escape to the external environment. Subsequent bacterial recovery illustrates an approximate bioburden reduction of 5log10for biofilms suspended in the drain, and 6log10for biofilms placed in the sink.ConclusionsPlasma-generated ozone is a safe and effective method for controlling bioburden in periodically wetted, otherwise inaccessible pipework and drains, both above and below the water line.Significance and Impact of StudyThe ozone generation system described has potential for controlling healthcare associated infections (HAIs) and infections linked to closed environments, such as cruise ships, from bacteria arising from waste water systems by aerosolization or splash-back. The method has additional benefits provided by an absence of toxic residues after application, reducing risks to users and the waste water system. Cost effectiveness is high, requiring minimal energy input from the electrical supply and only ambient air (no additional feedstock gas is necessary) to generate ozone.
A simple method for developing lysine targeted covalent protein reagents
Authors: Gabizon Ronen , Tivon Barr , Reddi Rambabu N. , van den Oetelaar Maxime C. M. , Amartely Hadar , Cossar Peter J. , Ottmann Christian , London Nir 
Published: August 2023

AbstractThere is a growing demand for covalent tool compounds and chemical probes to investigate and perturb protein function and dysregulation. The combination of a covalent electrophile with a peptide or protein-based scaffold with an extended binding footprint enables the targeting of shallow protein surfaces, not typically addressable using small molecules. However, to fully exploit the potential of electrophilic proteins or peptides there is a need for versatile approaches to convert native peptide sequences into covalent binders that can target a broad range of residues. Here we report protein-based thio-methacrylate esters - electrophiles with a diverse reactivity profile that can be installed easily on unprotected peptides and proteins via cysteine side chains, and react efficiently and selectively with cysteine and lysine side chains on the target. Guided by computational modeling, we designed and synthesized methacrylate phosphopeptides derived from 14-3-3-binding proteins and demonstrated these peptides irreversibly label 14-3-3σ via either lysine or cysteine residues, depending on the position of the electrophile. Methacrylate peptides targeting a conserved lysine residue exhibited pan-isoform binding of 14-3-3 proteins, and efficiently labeled 14-3-3 proteins in lysates, as well as secreted 14-3-3 extracellularly. The irreversible binding to the predicted target lysines were confirmed by proteomics and X-ray crystallography of the complexes. Finally, we applied this approach to develop protein-based covalent binders. A methacrylate-modified variant of the colicin E9 immunity protein irreversibly bound to the E9 DNAse, resulting in significantly higher thermal stability relative to the non-covalent complex. Our approach offers a simple and versatile route to convert peptides and proteins into potent covalent binders.
Limb regeneration is blastema dependent in a ladybird beetle,Cheilomenes sexmaculata(Fabricius)
Authors: Rawat Saumya , Rai Shriza , Mishra Geetanjali 
Published: August 2023

AbstractHolometabolous insects undergoes metamorphosis which involves an intercalated pupal stage between larva and adult. The body plan of the adult is established during pupal stage and larval systems are de-differentiated and reorganized in insects undergoing complete metamorphosis. In ladybird beetles, limbs amputated in larval stages are regenerated in adults. This occurs during pupation. Given that changes in pupa are akin to embryogenesis, does the lost limbs are redeveloped as a part of metamorphosis or has some pre-patterning initiated prior pupation? To study this we hypothesised that limb regeneration in a holometabolous ladybird beetles,Cheilomenes sexmaculatais the result of the recapitulation of the embryonic gene programs in the pupa. To test this, we exposed third larval stages ofC. sexmaculatato amputation and prior to amputation the tissues on the amputated site was scraped off every 24hrs. It was found that limb regeneration does not occur in the treatment where scrapping was done. Assuming that these epidermal cells correspond to blastema, for limb regeneration in ladybird beetles blastema is essential and does not occur in its absence.