bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cerebrospinal Fluid Pharmacokinetics of Nicardipine Following Intrathecal Administration in Subarachnoid Hemorrhage Patients
Authors: Sadan Ofer , Jeong Yoo-Seong , Cohen-Sadan Shany , Sathialingam Eashani , Buckley Erin M. , Kandiah Prem A. , Grossberg Jonathan A. , Asbury William , Jusko William J , Samuels Owen B. 
Published: October 2023

ABSTRACTSubarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH and contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 12 females) treated with IT nicardipine every 6 hours (n=8) or every 8 hours (n=8), which were subject to high-performance liquid chromatography for measurement of its CSF concentration. Our popPK analysis showed that the CSF PK of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time, with reliable parameter estimates (relative standard error < 50%). The intracranial pressure influenced both the total clearance and the central volume. Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine.
Multiple imputation assuming missing at random: auxiliary imputation variables that only predict missingness can increase bias due to data missing not at random
Authors: Curnow Elinor , Cornish Rosie P , Heron Jon E , Carpenter James R , Tilling Kate 
Published: October 2023

AbstractEpidemiological studies often have missing data, which are commonly handled by multiple imputation (MI). MI is valid (given correctly-specified models) if data are missing at random, conditional on the observed data, but not (unless additional information is available) if data are missing not at random (MNAR). In this paper we explore a previously-suggested strategy, namely, including an auxiliary variable predictive of missingness but not the missing data in the imputation model, when data are MNAR. We quantify, algebraically and by simulation, the magnitude of additional bias of the MI estimator, over and above any bias due to data MNAR, from including such an auxiliary variable. We demonstrate that where missingness is caused by the outcome, additional bias can be substantial when the outcome is partially observed. Furthermore, if missingness is caused by the outcome and the exposure, additional bias can be even larger, when either the outcome or exposure is partially observed. When using MI, it is important to identify, through a combination of data exploration and considering plausible casual diagrams and missingness mechanisms, the auxiliary variables most predictive of the missing data (in addition to all variables required for the analysis model and/or to minimise bias due to MNAR).
A qualitative analysis of community health worker perspectives on the implementation of the preconception and pregnancy phases of theBukhalirandomised controlled trial
Authors: Soepnel Larske M , Norris Shane A , Mabetha Khuthala , Motlhatlhedi Molebogeng , Nkosi Nokuthula , Lye Stephen , Draper Catherine E 
Published: October 2023

AbstractCommunity health workers (CHWs) play an important role in health systems in low– and middle-income countries, including South Africa.Bukhaliis a CHW-delivered intervention as part of a randomised controlled trial, to improve the health trajectories of young women in Soweto, South Africa. This study aimed to qualitatively explore factors influencing implementation of the preconception and pregnancy phases ofBukhali, from the perspective of the CHWs (Health Helpers, HHs) delivering the intervention. As part of theBukhalitrial process evaluation, three focus group discussions were conducted with the 13 HHs employed by the trial. A thematic approach was used to analyse the data, drawing on elements of a reflexive thematic and codebook approach. The following six themes were developed, representing factors impacting implementation of the HH roles: interaction with the existing public healthcare sector; participant perceptions of health; health literacy and language barriers; participants’ socioeconomic constraints; family, partner, and community views of trial components; and the HH-participant relationship. HHs reported uses of several trial-based tools to overcome implementation challenges, increasing their ability to implement their roles as planned. The relationship of trust between the HH and participants seemed to function as one important mechanism for impact. The findings supported a number of adaptations to the implementation ofBukhali, such as intensified trial-based follow-up of referrals that do not receive management at clinics, continued HH training and community engagement parallel to trial implementation, with an increased emphasis on health-related stigma and education.HH perspectives on intervention implementation highlighted adaptations relevant to theBukhaliintervention, other CHW-delivered preconception and pregnancy trials, and ‘real-world’ CHW roles, across three broad strategic areas: navigating and bridging healthcare systems, adaptability to individual participant needs, and navigating stigma around disease.
Feeding secondary fermentations with mammalian and fungal culture waste streams increases productivity and resource efficiency
Authors: Lynch Ciara , Cerrone Federico , O’Connor Kevin E , O’Connell David J 
Published: October 2023

AbstractThe evolution of the circular bioeconomy will require the realisation of new value from waste streams generated from all manufacturing processes. Bioprocessing of recombinant proteins and functional foods using animal and microbial fermentations are fast growing industries with increasing volumes of spent culture media waste resulting in significant resource inefficiency. Here Chinese hamster ovary cell spent media (CSM) andTrametes versicolorfungal cell spent media (FSM) were used as model waste streams to feedEscherichia coliin secondary fermentations. Expression of a recombinant fusion protein was used to measure the value of these streams as feedstuff.E. colicultures fed with either waste stream in bioreactors produced equivalent yields of the protein as those fed with rich microbiological media. Separately CSM was tested as a replacement feed for the fungal cell fermentation producing beta and alpha glucans. This waste-fed fermentation resulted in a 2-fold higher glucan yield than when using standard corn steep liquor feed. Quantitative analysis of the spent media content with mass spectrometry and hplc methods showed significant differences in elemental composition profiles, quantities of individual amino acids and carboxylic acids and levels of carbon sources. These findings underline the versatility ofE.coliin utilisation of waste media as a feedstuff and show that the range of applications of CHO cell culture media waste are not limited to feeding bacterial fermentation. Exploration of cellular bioprocesses that can efficiently use cell media waste as fermentation feed will be a valuable step towards increased resource efficiency in bioprocessing industries. (249/250).Significance StatementThe expanding range and scale of valuable biomolecular products developed with bioprocessing activities using animal and microbial cells is responsible for the production of hundreds of millions of litres of waste culture media annually. Recycling this waste stream has the potential to decrease the impact of the associated high water and energy consumption contributing to meeting targets for the Paris 2050 Agreement and UN Sustainable Development Goals. This work shows that waste media from distinct bioprocesses can be reused to sustain high-level recombinant protein production in a secondary fermentation and the notable finding that a waste media can add value to a secondary process by increasing its productivity. Efficient valorisation of waste media is an urgent and scientifically valuable objective. (120/120)
A purine salvage bottleneck leads to bacterial adenine cross-feeding
Authors: Chuang Ying-Chih , Haas Nicholas W. , Pepin Robert , Behringer Megan , Oda Yasuhiro , LaSarre Breah , Harwood Caroline S. , McKinlay James B. 
Published: October 2023

AbstractDiverse ecosystems host microbial relationships that are stabilized by nutrient cross-feeding. Cross-feeding can involve metabolites that should hold value for the producer. Externalization of such communally valuable metabolites is often unexpected and difficult to predict. Previously, we fortuitously discovered purine externalization byRhodopseudomonas palustrisby its ability to rescue growth of anEscherichia colipurine auxotroph. Here we found that anE. colipurine auxotroph can stably coexist withR. palustrisdue to purine cross-feeding. We identified the cross-fed purine as adenine. Adenine was externalized byR. palustrisunder diverse growth conditions. Computational models suggested that adenine externalization occurs via passive diffusion across the cytoplasmic membrane. RNAseq analysis led us to hypothesize that accumulation and externalization of adenine stems from an adenine salvage bottleneck at the enzyme encoded byapt. Ectopic expression ofapteliminated adenine externalization, supporting our hypothesis. A comparison of 49R. palustrisstrains suggested that purine externalization is relatively common, with 15 of the strains exhibiting the trait. Purine externalization was correlated with the genomic orientation ofaptorientation, butaptorientation alone could not explain adenine externalization in some strains. Our results provide a mechanistic understanding of how a communally valuable metabolite can participate in cross-feeding. Our findings also highlight the challenge in identifying genetic signatures for metabolite externalization.
Repressor sequestration activates translation of germ granule localized mRNA
Authors: Chen Ruoyu , Stainier William , Dufourt Jeremy , Lagha Mounia , Lehmann Ruth 
Published: October 2023

AbstractBiomolecular condensates organize and compartmentalize biochemical processes within cells1. Among these, ribonucleoprotein (RNP) granules are characterized as storage depots for translationally repressed mRNA2–8. Whether RNP granules can also activate translation and how such translation is achieved remains unclear9. This question is particularly relevant for embryonic germ granules, whose activity has been linked to germ cell fate10–13. Here, we use single-molecule imaging to show that embryonic germ cell RNP granules inDrosophilaare the sites of active translation fornanosmRNA. TranslatingnanosmRNA is oriented with the 5’end preferentially at the germ granule surface while the 3’UTR is buried within the granule. UntranslatednanosmRNAs remain internal within the granule. Quantitative analysis of translational kinetics demonstrates that germ granules activate translation by antagonizing translational repression rather than changing the rate or efficiency of translation. We generated separation-of-function mutations in the disordered linker region of the scaffold protein Oskar that specifically impedenanostranslation without affecting germ granule morphology or RNA localization. These mutations reveal thatnanostranslation is dependent on the sequestration of translational repressors within germ granules. Together, our findings show that RNP granules regulate localized protein synthesis through compartmentalized relief of translational repression raising the possibility that similar repressor-activator switches control translation in other condensates.
A single pair of pharyngeal neurons functions as a commander to reject high salt inDrosophila melanogaster
Authors: Sang Jiun , Dhakal Subash , Shrestha Bhanu , Nath Dharmendra Kumar , Kim Yunjung , Ganguly Anindya , Montell Craig , Lee Youngseok 
Published: October 2023

AbstractSalt is an essential nutrient for survival, while excessive NaCl can be detrimental. In the fruit fly,Drosophila melanogaster, internal taste organs in the pharynx are critical gatekeepers impacting the decision to accept or reject a food. Currently, our understanding of the mechanism through which pharyngeal gustatory receptor neurons (GRNs) sense high salt are rudimentary. Here, we found that a member of the ionotropic receptor family,Ir60b, is expressed exclusively in a pair of GRNs activated by high salt. Using a two-way choice assay (DrosoX) to measure ingestion volume, we demonstrate that IR60b and two coreceptors IR25a and IR76b, are required to prevent high salt consumption. Mutants lacking external taste organs but retaining the internal taste organs in the pharynx exhibit much higher salt avoidance than flies with all taste organs but missing the three IRs. Our findings highlight the vital role for IRs in a pharyngeal GRN to control ingestion of high salt.
Cut it out: Out-of-plane stresses in cell sheet folding ofVolvoxembryos
Authors: Haas Pierre A. , Höhn Stephanie S. M. H. 
Published: October 2023

AbstractThe folding of cellular monolayers pervades embryonic development and disease. It results from stresses out of the plane of the tissue, often caused by cell shape changes including cell wedging via apical constriction. These local cellular changes need not however be compatible with the global shape of the tissue. Such geometric incompatibilities lead to residual stresses that have out-of-plane components in curved tissues, but the mechanics and function of these out-of-plane stresses are poorly understood, perhaps because their quantification has proved challenging. Here, we overcome this difficulty by combining laser ablation experiments and a mechanical model to reveal that such out-of-plane residual stresses exist and also persist during the inversion of the spherical embryos of the green algaVolvox. We show how to quantify the mechanical properties of the curved tissue from its unfurling on ablation, and reproduce the tissue shape sequence at different developmental timepoints quantitatively by our mechanical model. Strikingly, this reveals not only clear mechanical signatures of out-of-plane stresses associated with cell shape changes away from those regions where cell wedging bends the tissue, but also indicates an adaptive response of the tissue to these stresses. Our results thus suggest that cell sheet folding is guided mechanically not only by cell wedging, but also by out-of-plane stresses from these additional cell shape changes.
Genetically- and spatially-defined basolateral amygdala neurons control food consumption and social interaction
Authors: Lim Hansol , Zhang Yue , Peters Christian , Straub Tobias , Mayer Johanna Luise , Klein Rüdiger 
Published: October 2023

AbstractThe basolateral amygdala (BLA) contains discrete neuronal circuits that integrate positive or negative emotional information and drive the appropriate innate and learned behaviors. Whether these circuits consist of genetically-identifiable and anatomically segregated neuron types, is poorly understood. Also, our understanding of the response patterns and behavioral spectra of genetically-identifiable BLA neurons is limited. Here, we classified 11 glutamatergic BLA cell clusters and found that several of them were anatomically segregated in lateral versus basal amygdala, and anterior versus posterior regions of the BLA. Two of these BLA subpopulations innately responded to valence-specific, whereas one responded to mixed - aversive and social - cues. Positive-valence BLA neurons promoted normal feeding, while mixed selectivity neurons promoted fear learning and social interactions. These findings enhance our understanding of cell type diversity and spatial organization of the BLA and the role of distinct BLA populations in representing valence-specific and mixed stimuli.HighlightsClassification of molecularly-defined glutamatergic neuron types in mouse BLA with distinct spatial expression patterns.BLALypd1neurons are positive-valence neurons innately responding to food and promoting normal feeding.BLAEtv1neurons innately represent aversive and social stimuli.BLAEtv1neurons promote fear learning and social interactions.
Detecting time-varying genetic effects in Alzheimer’s disease using a longitudinal GWAS model
Authors: Zhuang Xiaowei , Xu Gang , Amei Amei , Cordes Dietmar , Wang Zuoheng , Oh Edwin C. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: October 2023

AbstractBackgroundThe development and progression of Alzheimer’s disease (AD) is a complex process that can change over time, during which genetic influences on phenotypes may also fluctuate. Incorporating longitudinal phenotypes in genome wide association studies (GWAS) could help unmask genetic loci with time-varying effects. In this study, we incorporated a varying coefficient test in a longitudinal GWAS model to identify single nucleotide polymorphisms (SNPs) that may have time- or age-dependent effects in AD.MethodsGenotype data from 1,877 participants in the Alzheimer’s Neuroimaging Data Initiative (ADNI) were imputed using the Haplotype Reference Consortium (HRC) panel, resulting in 9,573,130 SNPs. Subjects’ longitudinal impairment status at each visit was considered as a binary and clinical phenotype. Participants’ composite standardized uptake value ratio (SUVR) derived from each longitudinal amyloid PET scan was considered as a continuous and biological phenotype. The retrospective varying coefficient mixed model association test (RVMMAT) was used in longitudinal GWAS to detect time-varying genetic effects on the impairment status and SUVR measures. Post-hoc analyses were performed on genome-wide significant SNPs, including 1) pathway analyses; 2) age-stratified genotypic comparisons and regression analyses; and 3) replication analyses using data from the National Alzheimer’s Coordinating Center (NACC).ResultsOur model identified 244 genome-wide significant SNPs that revealed time-varying genetic effects on the clinical impairment status in AD; among which, 12 SNPs on chromosome 19 were successfully replicated using data from NACC. Post-hoc age-stratified analyses indicated that for most of these 244 SNPs, the maximum genotypic effect on impairment status occurred between 70 to 80 years old, and then declined with age. Our model further identified 73 genome-wide significant SNPs associated with the temporal variation of amyloid accumulation. For these SNPs, an increasing genotypic effect on PET-SUVR was observed as participants’ age increased. Functional pathway analyses on significant SNPs for both phenotypes highlighted the involvement and disruption of immune responses- and neuroinflammation-related pathways in AD.ConclusionWe demonstrate that longitudinal GWAS models with time-varying coefficients can boost the statistical power in AD-GWAS. In addition, our analyses uncovered potential time-varying genetic variants on repeated measurements of clinical and biological phenotypes in AD.
Type II restriction of 2-aminoadenine (dZ) modified DNA and production of dZ-modified plasmid inE. coli
Authors: Yang Weiwei , Kuska Michael , Dai Nan , Ettwiller Laurence , Xu Shuang-yong 
Published: October 2023

AbstractThe modified DNA base 2,6 aminopurine (2-aminoadenine, (d)Z base) was originally found in phages to counteract host encoded restriction systems. However, only a limited number of restriction endonucleases (REases) have been tested on dZ-modified DNA. Herein we report the results of 147 REases activity on dZ-modified PCR DNA. Among the enzymes tested, 53.1% are resistant or partially resistant, and 46.9% are sensitive when the restriction sites contain 1 to 6 modified bases. Sites with 4-6 dZ substitutions are most likely resistant to Type II restriction. Our results support the notion that dZ-modified phage genomes are evolved to combat host- encoded restriction systems. dZ-modified DNA can also “slow down” phage T5 exonuclease degradation, but it has no effect on RecBCD digestion. When two genes for dZ biosynthesis and one gene for dATP hydrolysis fromSalmonellaphage PMBT28 (purZ(adenylosuccinate synthetase),datZ(dATP triphosphohydrolase), andmazZ((d)GTP-specific diphosphohydrolase) were cloned intoE. coliplasmid, dZ incorporation level reached 19-20% dZ/(dZ+dA). dZ level can be further increased to 28.9-44.3% with co-expression of a DNA polymerase gene from the same phage. High level of dZ incorporation in recombinant plasmid is possible by co-expression ofpurZ, mazZ, datZand phage DNA helicase,dpoZ (DNA polymerase) andssb(single-stranded DNA binding protein SSB). This work has a general interest for molecular biologists working on dZ DNA modification and restriction systems. It provides a foundation for future research on screening dZ-dependent Type IV restriction systems. The results presented herein may have implication in gene therapy utilizing dZ-modified DNA, provided that human RNA polymerase variants can efficiently perform transcription from a dZ-modified template.
Bidirectional Generative Adversarial Representation Learning for Natural Stimulus Synthesis
Authors: Reilly Johnny , Goodwin John D. , Lu Sihao , Kozlov Andriy S. 
Published: October 2023

AbstractThousands of species use vocal signals to communicate with one another. Vocalisations carry rich information, yet characterising and analysing these complex, high-dimensional signals is difficult and prone to human bias. Moreover, animal vocalisations are ethologically relevant stimuli whose representation by auditory neurons is an important subject of research in sensory neuroscience. A method that can efficiently generate naturalistic vocalisation waveforms would offer an unlimited supply of stimuli with which to probe neuronal computations. While unsupervised learning methods allow for the projection of vocalisations into low-dimensional latent spaces learned from the waveforms themselves, and generative modelling allows for the synthesis of novel vocalisations for use in downstream tasks, there is currently no method that would combine these tasks to produce naturalistic vocalisation waveforms for stimulus playback. In this paper, we demonstrate BiWaveGAN: a bidirectional Generative Adversarial Network (GAN) capable of learning a latent representation of ultrasonic vocalisations (USVs) from mice. We show that BiWaveGAN can be used to generate, and interpolate between, realistic vocalisation waveforms. We then use these synthesised stimuli along with natural USVs to probe the sensory input space of mouse auditory cortical neurons. We show that stimuli generated from our method evoke neuronal responses as effectively as real vocalisations, and produce receptive fields with the same predictive power. BiWaveGAN is not restricted to mouse USVs but can be used to synthesise naturalistic vocalisations of any animal species and interpolate between vocalisations of the same or different species, which could be useful for probing categorical boundaries in representations of ethologically relevant auditory signals.