bluuebunny/crossref_metadata_2025_split huggingface dataset:
ThePlasmodium falciparumartemisinin resistance-associated protein Kelch 13 is required for formation of normal cytostomes
Authors: Tutor Madel V. , Shami Gerald J. , Siddiqui Ghizal , Creek Darren J. , Tilley Leann , Ralph Stuart A. 
Published: March 2023

AbstractArtemisinin (ART) is a quick-killing and effective antimalarial activated by the haem derived from haemoglobin digestion. Mutations in the parasite’s Kelch 13 (K13) protein compromise the efficacy of this drug. Recent studies indicate an undefined role for K13 in haemoglobin uptake. Here, we show that K13 is associated with the collar that constricts cytostomal invaginations required for the parasite to ingest host cytosol. Induced mislocalisation of K13 led to the formation of atypical invaginations lacking the cytostomal ring and constricted neck normally associated with cytostomes. Moreover, the levels of haemoglobin degradation products, haem and haemozoin, are decreased when K13 is inactivated. Our findings demonstrate that K13 is required for normal formation and/or stabilisation of the cytostome, and thereby the parasite’s uptake of haemoglobin. This is consistent with perturbation of K13 function leading to decreased activation of ART and consequently, reduced killing.Significance StatementArtemisinin-resistant parasites contain mutations in the gene encoding the Kelch 13 protein (K13). How K13 mutations result in artemisinin resistance is unclear. Here, we present evidence that normal K13 is required for the formation of the cytostome, a specialised parasite feeding apparatus used to endocytose host cell haemoglobin. Our results suggest that artemisinin resistance is due to a decrease in artemisinin activation brought about by a decrease in efficiency of haemoglobin uptake and consequently reduced production of haem.
Medial Prefrontal Cortex Serotonin Input Regulates Cognitive Flexibility in Mice
Authors: Morgan Ashlea A. , Alves Nuno D. , Stevens Gregory S. , Yeasmin Tamanna T. , Mackay Alexandra , Power Saige , Sargin Derya , Hanna Carla , Adib Arwa L. , Ziolkowski-Blake Annette , Lambe Evelyn K. , Ansorge Mark S. 
Published: March 2023

AbstractThe medial prefrontal cortex (mPFC) regulates cognitive flexibility and emotional behavior. Neurons that release serotonin project to the mPFC, and serotonergic drugs influence emotion and cognition. Yet, the specific roles of endogenous serotonin release in the mPFC on neurophysiology and behavior are unknown. We show that axonal serotonin release in the mPFC directly inhibits the major mPFC output neurons. In serotonergic neurons projecting from the dorsal raphe to the mPFC, we find endogenous activity signatures pre-reward retrieval and at reward retrieval during a cognitive flexibility task.In vivooptogenetic activation of this pathway during pre-reward retrieval selectively improved extradimensional rule shift performance while inhibition impaired it, demonstrating sufficiency and necessity for mPFC serotonin release in cognitive flexibility. Locomotor activity and anxiety-like behavior were not affected by either optogenetic manipulation. Collectively, our data reveal a powerful and specific modulatory role of endogenous serotonin release from dorsal raphe-to-mPFC projecting neurons in cognitive flexibility.
Adaptation mechanisms ofListeria monocytogenesto quaternary ammonium compounds
Authors: Schulz Lisa Maria , Dreier Fabienne , de Sousa Miranda Lisa Marie , Rismondo Jeanine 
Published: March 2023

AbstractListeria monocytogenesis ubiquitously found in nature and can easily enter food-processing facilities due to contaminations of raw materials. Several countermeasures are used to combat contamination of food products, for instance the use of disinfectants that contain quaternary ammonium compounds, such as benzalkonium chloride (BAC) and cetyltrimethylammonium bromide (CTAB). In this study, we assessed the potential of the commonly used wildtype strain EGD-e to adapt to BAC and CTAB under laboratory growth conditions. All BAC-tolerant suppressors exclusively carried mutations infepRor its promoter region likely resulting in the overproduction of the efflux pump FepA. In contrast, CTAB- tolerance was associated with mutations insugR, which regulates the expression of the efflux pumps SugE1 and SugE2.L. monocytogenesstrains lacking either FepA or SugE1/2 could still acquire tolerance towards BAC and CTAB. Genomic analysis revealed that the overproduction of the remaining efflux system could compensate for the deleted one. Even in the absence of both efflux systems, tolerant strains could be isolated, which all carried mutations in the diacylglycerol kinase encoding genelmo1753(dgkB). DgkB converts diacylglycerol to phosphatidic acid, which is subsequently re-used for the synthesis of phospholipids suggesting that alterations in membrane composition could be the third adaptation mechanism.Originality-Significance StatementSurvival and proliferation ofListeria monocytogenesin the food industry is an ongoing concern, and while there are various countermeasures to combat contamination of food products, the pathogen still successfully manages to withstand the harsh conditions present in food-processing facilities, resulting in reoccurring outbreaks, subsequent infection, and disease. To counteract the spread ofL. monocytogenesit is crucial to understand and elucidate the underlying mechanism that permit their successful evasion. We here present various adaptation mechanisms ofL. monocytogenesto withstand two important quaternary ammonium compounds.
Specificity and mechanism of 1,6 hexanediol-induced disruption of nuclear transport
Authors: Barrientos Elizabeth C. Riquelme , Otto Tegan A. , Mouton Sara N. , Steen Anton , Veenhoff Liesbeth M. 
Published: March 2023

ABSTRACTSelective transport through the nuclear pore complex (NPC) depends on the dynamic binding of the intrinsically disordered components of the NPC, the FG-nups, with each other and with nuclear transport receptors (NTRs). Hydrophobic interactions with the phenylalanines of FG-nups are critical for this dynamic binding. 1,6-hexanediol (1,6HD), is an aliphatic alcohol that interferes with hydrophobic interactions. Here we assessed the specificity and mechanism by which 1,6HD disrupts the permeability barrier of NPCs in live baker’s yeast cells. Exposure to 1,6HD (10 min, 0-5%) leads to gradual loss of the NPC permeability. This is likely a direct effect on the nuclear transport machinery as cell viability, the pH and ATP levels in the cytosol, as well as the appearance of mitochondria, Golgi, peroxisomes, ER, vacuoles, plasma membrane, nucleolus, secretory pathway and stress granules are not notably changed. There are however effects on the cytoskeleton and Hsp104 to be noted. While 1,6HD treatment does not lead to dissociation or degradation of NPC subunits, a massive relocation of multiple NTRs from NPCs does occur. This displacement quantitatively correlates with the increased passive permeability of NPCs. The loss of NTRs and associated cargo will present a major change in the macromolecular crowding and composition and hence the physicochemical properties of the central channel. We conclude that 1,6HD provides a surprisingly specific intervention to temporarily permeate NPCs and we present evidence that the mechanism includes release of NTRs from the NPCs.
Structural basis for activation of glutaminase
Authors: Guo Chen-Jun , Wang Zi-Xuan , Liu Ji-Long 
Published: March 2023

AbstractGlutaminase is a rate-limiting enzyme in glutaminolysis, which produces glutamate from glutamine and enters the TCA cycle[1]. In addition, it plays a key role in redox homeostasis[2], autophagy[3], immune system regulation[4], central nervous system maintenance[5], and senolysis[6]. Therefore, the allosteric regulation of glutaminase is a fascinating topic that has broad implications for our understanding of glutamine metabolism and related diseases[7–9]. Phosphate was discovered as a natural agonist for glutaminase in 1947[10], but the structural basis and mechanism for this regulation remains unclear. Using cryo-electron microscopy, here we determine the structure of human glutaminase with phosphate. This structure allows us to capture phosphate binding at the dimer-dimer interface at near atomic resolution, revealing an allosteric activation mechanism by remodelling the catalytic pocket. Surprisingly, we find that phosphate antagonizes BPTES (a classical antagonist) and CB-839 (the current subject of several phase II clinical trials). Accurate identification of phosphate binding sites lays the foundation for the design of glutaminase agonists and antagonists with broad pharmaceutical significance.
Preterm birth and cardiometabolic health trajectories from birth to adulthood: the Avon Longitudinal Study of Parents and Children
Authors: Clayton Gemma L , Howe Laura D , O’Keeffe Linda M , Lewandowski Adam J , Lawlor Deborah A , Fraser Abigail 
Published: March 2023

AbstractBackgroundAdults who were born prematurely (<37 weeks gestation) are at increased cardiovascular disease risk, but it is unclear when in the life course this risk emerges. Our aim was to compare trajectories of multiple cardiometabolic risk factors from childhood to early adulthood between those who had and had not been born preterm.MethodsMultilevel models were used to compare trajectories from early childhood (ranging from birth to 9 years) to age 25 years of BMI, fat mass, lean mass, systolic and diastolic blood pressure (BP), lipids, glucose and insulin, between participants born preterm (N=311-733, range 25-36 completed weeks gestation) and term (N=5365-12097) in a contemporary UK birth cohort study. We also investigated gestational age as a continuum.ResultsIn children born preterm (versus term), systolic and diastolic BP were higher at age 7 (mean predicted differences 0.6mmHg; 95%CI -0.3, 1.5 and 0.6mmHg; 95%CI 0.03, 1.3, respectively). By age 25 years, the difference in SBP persisted (1.4, 95%CI -0.1, 2.9 mmHg) and in DBP (−0.2, 95%CI -1.3, 0.9 mmHg) disappeared. Participants born preterm (versus term) had lower BMI between 7 and 18 years, but by age 25, there was no difference. Lean mass and fat mass (measured from age 9 only) trajectories were consistent with BMI. HDL-c was higher, and triglycerides lower at birth in those born preterm, but this difference also disappeared by 25 years. There was no evidence of differences in glucose and insulin between participants born preterm compared to term.ConclusionsThere were few, modest differences in cardiometabolic health measures during early life in those born preterm versus term. All disappeared by age 25, except the small difference in SBP. Longer follow-up is needed to establish if and when trajectories of measures of cardiometabolic health in term and preterm born people diverge.Clinical perspectiveWhat is new?Whether life course trajectories of commonly assessed cardiovascular disease (CVD) risk factors such as blood pressure, are different in people born preterm vs those born at term, is unknown.By age 25, we generally found no evidence of differences between people born preterm and term on measures of cardiometabolic health except that systolic blood pressure was modestly higher in those born preterm. We also observed more favourable outcomes with lower adiposity measures between ages 9 and 18 years.Clinical implicationsThe reported increased risk of CVD in people born preterm is not apparent in early adulthood.Whilst it may emerge in later life, our results suggest no justification for CVD screening using ‘classic’ risk factors in young adults based on their gestational age.Further work to replicate these findings in other independent cohorts and studies with follow-up into mid life are required to examine when associations emerge.
Age modulates protein-outcome associations in deceased donor kidneys
Authors: Charles Philip D , Vaughan Rebecca H , Fawaz Sarah , Davis Simon , Joshi Priyanka , Vendrell Iolanda , Fischer Roman , Kessler Benedikt M , Sharples Edward J , Santos Alberto , Ploeg Rutger J , Kaisar Maria 
Published: March 2023

ABSTRACTBackgroundOrgan availability limits kidney transplantation, the best treatment for end-stage kidney disease. Globally, deceased donor acceptance criteria have been relaxed to include older donors, which comes with a higher risk of inferior posttransplant outcomes. Donor age, although negatively impacts transplant outcomes, lacks granularity in predicting graft dysfunction. Better donor kidney assessment and characterization of the biological mechanisms underlying age-associated donor organ damage and transplant outcomes is key to improving donor kidney utilisation and transplant longevity.Methods185 deceased pretransplant biopsies (from brain and circulatory death donors aged 18-78 years) were obtained from the Quality in Organ Donation (QUOD) biobank and proteomic profiles were acquired by mass spectrometry. Machine learning exploration using prediction rule ensembles guided LASSO regression modeling of kidney proteomes that identified protein signatures and biological mechanisms associated with 12-m posttransplant outcome. Data modeling was validated on held-out data and contextualised against published spatially resolved kidney injury related transcriptomes.ResultsOur analysis highlighted that outcomes were best modeled using combination of donor age and protein abundance signatures, revealing 539 proteins with these characteristics. Modeled age:protein interactions demonstrated stronger associations with transplant outcomes than age and protein alone and revealed mechanisms of kidney injury including metabolic changes and innate immune responses correlated with poor outcome. Comparison to single-cell transcriptome data suggests protein-outcome associations to specific cell types.ConclusionsMolecular signatures resulted from integration of donor age and proteomic profiles in deceased donor kidney biopsies offer the potential to develop improved pretransplant organ assessment and aid decisions on perfusion interventions.
Opportunities to improve nutrition delivery in hospital after discharge from an intensive care unit: A mixed methods analysis
Authors: Vollam Sarah , Gustafson Owen , Morgan Lauren , Pattison Natalie , Redfern Oliver , Thomas Hilary , Watkinson Peter 
Published: March 2023

ABSTRACTBackground and AimsThough adequate nutrition following critical illness is fundamental to rehabilitation, it is poorly provided. To inform interventions to improve nutrition support for patients discharged from an intensive care unit (ICU), we aimed to document remediable problems in nutrition management on general hospital wards, and the context for these problems.MethodsThis work forms part of a larger mixed methods study: REcovery FoLlowing intensivE Care Treatment (REFLECT). From three NHS hospitals, chosen to represent different hospital settings, we conducted in-depth reviews of 20 cases where in-hospital death after ICU discharge was judged ‘probably avoidable’ and 20 cases where patients survived to hospital discharge. We interviewed 55 patients, family members and staff about their experiences of post-ICU ward care. From these primary data we extracted information related to nutrition provision to develop a process map of how enteral feeding is delivered to patients on hospital wards after ICU discharge.ResultsProblems with nutrition delivery were common (81 problems in 20/40 cases), mostly (70/81) in patients whose death was judged “probably avoidable”. Common issues included failure to monitor nutritional intake, delays in dietician/nutritional support referrals, removal of enteral feeding tubes before oral intake was established, and poor management of enteral nutrition delivery. Staff identified workload related to the high care needs of post-ICU patients as contributing to these problems in nutrition delivery. The process map of enteral feeding delivery demonstrated that local policy for tube placement confirmation risked prolonged system-related delays to administering naso-gastric feed, significantly affecting the volume of feed delivered to patients.ConclusionsUsing a novel mixed methods approach, we identified problems throughout the process of delivering nutritional support, which had profound consequences for post-ICU patients. We demonstrated the importance of multi-professional collaboration in delivering enteral nutrition. Improving collaborative working processes within the ward system may ensure timely confirmation of correct nasogastric tube placement, and support safe feeding. Addressing the common problems in post-ICU nutritional support we identified may support improved nutritional delivery and potentially enhance recovery from critical illness.Study registrationISRCTN:14658054
Neural representations in visual and parietal cortex differentiate between imagined, perceived, and illusory experiences
Authors: Li Siyi , Zeng Xuemei , Shao Zhujun , Yu Qing 
Published: March 2023

AbstractHumans constantly receive massive amounts of information, both perceived from the external environment and imagined from the internal world. To function properly, the brain needs to correctly identify the origin of information being processed. Recent work has suggested common neural substrates for perception and imagery. However, it has remained unclear how the brain differentiates between external and internal experiences with shared neural codes. Here we tested this question by systematically investigating the neural processes underlying both the generation and maintenance of information from voluntary imagery, veridical perception, and illusion. The inclusion of illusion allowed us to differentiate between objective and subjective internality: while illusion has an objectively internal origin and can be viewed as involuntary imagery, it is also subjectively perceived as having an external origin like perception. Combining fMRI, eye-tracking, multivariate decoding and encoding approaches, we observed superior orientation representations in parietal cortex during imagery compared to perception, and conversely in early visual cortex. This imagery dominance gradually developed along a posterior-to-anterior cortical hierarchy from early visual to parietal cortex, emerged in the early epoch of imagery and sustained into the delay epoch, and persisted across varied imagined contents. Moreover, representational strength of illusion was more comparable to imagery in early visual cortex, but more comparable to perception in parietal cortex, suggesting content-specific representations in parietal cortex differentiate between subjectively internal and external experiences, as opposed to early visual cortex. These findings together support a domain-general engagement of parietal cortex in the generation and maintenance of internally-generated experience.Significance StatementHow does the brain differentiate between imagined and perceived experiences? Combining fMRI, eye-tracking, multivariate decoding and encoding approaches, the current study revealed enhanced stimulus-specific representations in visual imagery originating from IPS, supporting the subjective experience of imagery. This neural principle was further validated by evidence from visual illusion, wherein illusion resembled perception and imagery at different levels of cortical hierarchy. Our findings provide direct evidence for the critical role of parietal cortex as a domain-general source region for the generation and maintenance of content-specific imagery, and offer new insights into the neural mechanisms underlying the differentiation between subjectively internal and external experiences.
Explicit Modelling of Antibody Levels for Infectious Disease Simulations in the Context of SARS-CoV-2
Authors: Müller Sebastian A. , Paltra Sydney , Rehmann Jakob , Nagel Kai , Conrad Tim O.F. 
Published: March 2023

SummaryMeasurable levels of immunoglobulin G antibodies develop after infections with and vaccinations against SARS-CoV-2. These antibodies are temporarily dynamic; due to waning, antibody levels will drop below detection thresholds over time. As a result, epidemiological studies could underestimate population protection, given that antibodies are a marker for protective immunity.During the COVID-19 pandemic, multiple models predicting infection dynamics were used by policymakers to plan public health policies. Explicitly integrating antibody and waning effects into the models is crucial for reliable calculations of individual infection risk. However, only few approaches have been suggested that explicitly treat these effects.This paper presents a methodology that explicitly models antibody levels and the resulting protection against infection for individuals within an agent-based model. This approach can be integrated in general frameworks, allowing complex population studies with explicit antibody and waning effects. We demonstrate the usefulness of our model in two use cases.
Bi-objective optimization framework for prefabricated construction service combination selection using genetic simulated annealing algorithm
Authors: Du Qiang , Qi Xiaomin , Zou Patrick X.W. , Zhang Yanmin 
Published: March 2023

PurposeThe purpose of this paper is to develop a bi-objective optimization framework to select prefabricated construction service composition. An improved algorithm-genetic simulated annealing algorithm (GSA) is employed to demonstrate the application of the framework.Design/methodology/approachThe weighted aggregate multi-dimensional collaborative relationship is used to quantitatively evaluate the synergistic effect. The quality of service is measured using the same method. The research proposed a service combination selection framework of prefabricated construction that comprehensively considers the quality of service and synergistic effect. The framework is demonstrated by using a GSA that can accept poor solutions with a certain probability. Furthermore, GSA is compared with the genetic algorithm (GA), simulated annealing algorithm (SA) and particle swarm optimization algorithm (PSO) to validate the performance.FindingsThe results indicated that GSA has the largest optimal fitness value and synergistic effect compared with other algorithms, and the convergence time and convergence iteration of the improved algorithm are generally at a low level.Originality/valueThe contribution of this study is that the proposed framework enables project managers to clarify the interactions of the prefabricated construction process and provides guidance for project collaborative management. In addition, GSA helps to improve the probability of successful collaboration between potential partners, therefore enhancing client satisfaction.