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Introduction: This article investigates funding sources reported by authors of open access (OA) articles at four R1 (doctoral-granting institutions in the United States with very high research activity) universities, along with these authors’ perceptions of Article Processing Charges (APCs). The study suggests a cognitive dissonance among many respondents, in which there appears to be a desire and willingness to participate in OA publishing, which is at odds with a sense of unreasonableness and an uneven distribution of the ability of researchers to participate. Literature review: Much of the literature on APCs centers on rising prices, how commercial publishers profit from this model, and the resulting inequities in OA publishing. Some information exists about resources for funding APCs, including grant funding, library programs, and fee waivers. Methods: We surveyed authors who published an OA article in the calendar year 2022. The survey asked whether there was an APC, the funding source for the fee, and the author’s perception of the reasonableness of APC prices and their relative ability to pay compared with their peers. Results: From 321 total respondents, grant funding was the largest source of APC funding, and authors reported fees of over $1,500 in U.S. dollars as unreasonable. Discussion: This study confirms the hypothesis that external grants are the primary support for authors paying APCs, and beyond that, authors use a variety of sources to support their publishing fees. Respondents characterized APCs in general as unreasonable for less well-resourced colleagues. Conclusion: Though authors were generally able to find funding or have fees waived, they perceive a threshold of reasonableness for APCs.

Introduction: This article investigates funding sources reported by authors of open access (OA) articles at four R1 (doctoral-granting institutions in the United States with very high research activity) universities, along with these authors' perceptions of Article Processing Charges (APCs). The study suggests a cognitive dissonance among many respondents, in which there appears to be a desire and willingness to participate in OA publishing, which is at odds with a sense of unreasonableness and an uneven distribution of the ability of researchers to participate. Literature review: Much of the literature on APCs centers on rising prices, how commercial publishers profit from this model, and the resulting inequities in OA publishing. Some information exists about resources for funding APCs, including grant funding, library programs, and fee waivers. Methods: We surveyed authors who published an OA article in the calendar year 2022. The survey asked whether there was an APC, the funding source for the fee, and the author's perception of the reasonableness of APC prices and their relative ability to pay compared with their peers. Results: From 321 total respondents, grant funding was the largest source of APC funding, and authors reported fees of over $1,500 in U.S. dollars as unreasonable. Discussion: This study confirms the hypothesis that external grants are the primary support for authors paying APCs, and beyond that, authors use a variety of sources to support their publishing fees. Respondents characterized APCs in general as unreasonable for less well-resourced colleagues. Conclusion: Though authors were generally able to find funding or have fees waived, they perceive a threshold of reasonableness for APCs.

Psychosocial stress has profound effects on the body, including the immune system and the brain 1 , 2 . Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD) 3 , the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders. Serum MMP8 is increased in stress-susceptible mice following chronic stress and leads to brain structure and behavioural changes in mice.

We report an improved draft nucleotide sequence of the 2.3-gigabase genome of maize, an important crop plant and model for biological research. Over 32,000 genes were predicted, of which 99.8% were placed on reference chromosomes. Nearly 85% of the genome is composed of hundreds of families of transposable elements, dispersed nonuniformly across the genome. These were responsible for the capture and amplification of numerous gene fragments and affect the composition, sizes, and positions of centromeres. We also report on the correlation of methylation-poor regions with Mu transposon insertions and recombination, and copy number variants with insertions and/or deletions, as well as how uneven gene losses between duplicated regions were involved in returning an ancient allotetraploid to a genetically diploid state. These analyses inform and set the stage for further investigations to improve our understanding of the domestication and agricultural improvements of maize.

Background and Objective Pediatric dosing of enoxaparin was derived based on extrapolation of the adult therapeutic range to children. However, a large fraction of children do not achieve therapeutic anticoagulation with initial dosing. We aim to use real-world anti-Xa data obtained from children receiving enoxaparin per standard of care to characterize the population pharmacokinetics (PopPK). Methods A PopPK analysis was performed using NONMEM, and a stepwise covariate modeling approach was applied for the covariate selection. The final PopPK model, developed with data from 1293 patients ranging in age from 1 day to 18 years, was used to simulate enoxaparin subcutaneous dosing for prophylaxis and treatment based on total body weight (0–18 years, TBW) or fat-free mass (2–18 years, FFM). Simulated exposures in children with obesity (body mass index percentile ≥95th percentile) were compared with those without obesity. Results A linear, one-compartment PopPK model that included allometric scaling using TBW (<2 years) or FFM (≥2 years) characterized the enoxaparin pharmacokinetic data. In addition, serum creatinine was identified as a significant covariate influencing clearance. Simulations indicated that in patients aged <2 years, the recommended 1.5 mg/kg TBW-based dosing achieves therapeutic simulated concentrations. In pediatric patients aged ≥2 years, the recommended 1.0 mg/kg dose resulted in exposures more comparable in children with and without obesity when FFM weight-based dosing was applied. Conclusion Using real-world data and PopPK modeling, enoxaparin’s pharmacokinetics were characterized in pediatric patients. Using FFM and twice-daily dosing might reduce the risk of overdosing, especially in children with obesity.

ΔFOSB, an unusually stable member of the AP1 family of transcription factors, mediates long-term maladaptations that play a key role in the pathogenesis of drug addiction, cognitive decline, dyskinesias, and several other chronic neurological and psychiatric conditions. We have recently identified that 2-phenoxybenzenesulfonic acid-containing compounds disrupt the binding of ΔFOSB to DNA in cell-based assays, and one such compound, JPC0661, disrupts ΔFOSB binding to genomic DNA in mouse brain with partial efficiency. JPC0661 binds to a groove outside of the DNA-binding cleft of the ΔFOSB/JUND bZIP heterodimer in the co-crystal structure. Here, we generated a panel of analogs of JPC0661 with the goal of establishing structure-activity relationships and improving its efficacy by replacing the amino-pyrazolone cap moiety with various substituents. We show that one such analog, YL0441, disrupts the binding of ΔFOSB to DNA and , and suppresses ΔFOSB-function in cell-based assays. Importantly, infusion of YL0441 into the hippocampus of APP mice (a mouse model for Alzheimer's disease) leads to virtually complete loss of ΔFOSB bound to genomic DNA by CUT&RUN sequencing. Our findings corroborate that DNA binding/release of AP1 transcription factors can be controlled via small molecules, even by analogs of a compound that binds to a groove outside of the DNA-binding cleft, and that our lead can be optimized via medicinal chemistry to yield a highly efficacious inhibitor of ΔFOSB function . These findings define a strategy to design small-molecule inhibitors for other AP1- and AP1-related transcription factors. We demonstrate the creation of a highly effective inhibitor, YL0441, of ΔFOSB, an AP1 transcription factor, which decreases the number of ΔFOSB-bound sites to genomic DNA by ∼94% upon infusion to the hippocampus of APP mice, a mouse model for Alzheimer's disease. This work generates a highly novel probe compound to assess the therapeutic value of ΔFOSB , a transcription factor with a critical role in mediating long-term changes in gene expression in several neuropsychiatric disorders in addition to Alzheimer's disease, including drug addiction, seizure-related cognitive decline, and dyskinesias.

Drug addiction is characterized by neuronal adaptations that support a shift from goal-directed behaviors to habitual, compulsive drug-seeking with persistent effects on cognition and decision-making. Emerging evidence increasingly indicates that astrocytes are also involved in nervous system disorders, including addiction, but the cocaine-induced astrocyte-specific transcriptome has not yet been investigated. We utilized whole cell sorting of astrocytes, RNA-sequencing, and bioinformatic approaches to characterize the astrocyte transcriptome in the nucleus accumbens (NAc), a key brain region involved in reward-processing, following cocaine self-administration, prolonged abstinence, and \"relapse\" in male mice. We found that astrocytes exhibit robust and contextually-specific transcriptional signatures that converge strongly with human cocaine use disorder. Bioinformatic analysis revealed CREB as a highly ranked predicted upstream regulator of cocaine-induced transcriptional regulation in NAc astrocytes, and CUT&RUN-sequencing mapped increased CREB binding across the astrocyte genome in response to cocaine. Viral-mediated manipulation of CREB activity selectively in NAc astrocytes, in combination with several measures of addiction-related behaviors including conditioned place preference and self-administration, revealed that astrocytic CREB increases the rewarding and reinforcing properties of cocaine. This effect is sex-specific, with no change in astrocytic CREB activity or CPP found in females. Subsequent experiments identify potential molecular mechanisms of astrocytic CREB's influence through modulating astrocytic Ca signaling in response to cocaine. Finally, we show that astrocytic CREB selectively modulates D1-type medium spiny neurons in NAc to control cocaine-related behaviors. Together, these data demonstrate that the astrocyte transcriptome responds robustly to cocaine and that CREB mediates cocaine's effects on gene expression in astrocytes, with consequent effects on neuronal activity and rewarding responses to the drug.