bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics of Cerebrospinal Fluid in Autism Spectrum Disorder - A Systematic Review
Authors: Srivastava Vandana , O’Reilly Christian
Published: February 2024

Autism Spectrum Disorder (ASD) is a range of neurodevelopmental conditions characterized by impaired social interaction, learning, and restricted or repetitive behaviors. The underlying causes of ASD are still debated, but researchers have found many physiological traits like gut problems and impaired immune system, to help understand the etiology of ASD. Cerebrospinal fluid (CSF) plays a critical role in maintaining the homeostasis of the neuronal environment and has, therefore, been analyzed in multiple conditions impacting the central nervous system. The study of CSF is crucial to understanding neurological disorders as its composition changes with the disorders, and these changes may indicate various disorder-related physiological mechanisms. For this systematic review, we searched the PubMed database for studies published between 1977 and 2023 and selected 45 studies after manual screening. We took stock of the evidence supporting the hypothesis that ASD alters the properties and composition of CSF. We systematically report on the different attributes of CSF in the ASD population that could be potential biomarkers and assist in understanding the origins and progression of ASD.

We found that in CSF, immune markers, proteins, extra-axial CSF, folate, oxytocin, and vasopressin showed changes in ASD compared to the neurotypicals. We observed many gaps in the literature due to variations in the age and sample size, bias in sex-based reporting of results, and a handful of studies on ASD adults. Our review highlights the need for more research on CSF in autism spectrum disorder to improve understanding of the disorder and identify CSF biomarkers.
Causal role of medial superior frontal cortex on enhancing neural information flow and self-agency judgments in the self-agency network
Authors: Jia Yingxin , Kudo Kiwamu , Jariwala Namasvi , Tarapore Phiroz , Nagarajan Srikantan , Subramaniam Karuna
Published: February 2024

Self-agency is being aware of oneself as the agent of one’s thoughts and actions. Self-agency is necessary for successful interactions with the outside world (reality-monitoring). Prior research has shown that the medial superior prefrontal gyri (mPFC/SFG) may represent one neural correlate underlying self-agency judgments. However, the causal relationship remains unknown. Here, we applied high-frequency 10Hz repetitive transcranial magnetic stimulation (rTMS) to modulate the excitability of the mPFC/SFG site that we have previously shown to mediate self-agency. For the first time, we delineatecausalneural mechanisms, revealing precisely how rTMS modulates SFG excitability and impactsdirectionalneural information flow in the self-agency network by implementing innovative magnetoencephalography (MEG) phase-transfer entropy (PTE) metrics, measured from pre-to-post rTMS. We found that, compared to control rTMS, enhancing SFG excitability by rTMS induced significant increases in information flow between SFG and specific cingulate and paracentral regions in the self-agency network in delta-theta, alpha, and gamma bands, which predicted improved self-agency judgments. This is the first multimodal imaging study in which we implement MEG PTE metrics of 5D imaging of space, frequency and time, to provide cutting-edge analyses of thecausalneural mechanisms of how rTMS enhances SFG excitability and improves neural information flow between distinct regions in the self-agency network to potentiate improved self-agency judgments. Our findings provide a novel perspective for investigatingcausalneural mechanisms underlying self-agency and create a path towards developing novel neuromodulation interventions to improve self-agency that will be particularly useful for patients with psychosis who exhibit severe impairments in self-agency.
Pulsatility analysis of the circle of Willis
Authors: Voss Henning U. , Razlighi Qolamreza R.
Published: February 2024

Purpose

To evaluate the phenomenological significance of cerebral blood pulsatility imaging in aging research.

Methods

N = 38 subjects aged from 20 to 72 years of age (24 females) were imaged with ultrafast MRI with a sampling rate of 100 ms and simultaneous acquisition of pulse oximetry data. Of these, 28 subjects had acceptable MRI and pulse data, with 16 subjects between 20 and 28 years of age, and 12 subjects between 61 and 72 years of age. Pulse amplitude in the circle of Willis was assessed with the recently developed method of analytic phase projection to extract blood volume waveforms with an effective sampling rate of about 0.3 ms.

Results

Arteries in the circle of Willis showed pulsatility in the MRI for both the young and old age groups. Pulse amplitude in the circle of Willis significantly increased with age (p = 0.01) but was independent of gender, heart rate, and head motion during MRI.

Discussion and conclusion

Increased pulse wave amplitude in the circle of Willis in the elderly suggests a phenomenological significance of cerebral blood pulsatility imaging in aging research. The physiologic origin of increased pulse amplitude (increased pulse pressure vs. change in arterial morphology vs. re-shaping of pulse waveforms caused by the heart) requires further investigation.
Strategy for identifying insulin pump use in Clinical Practice Research Datalink GOLD
Authors: Persson Rebecca , Sponholtz Todd , Baak Brenda N , Jick Susan S
Published: February 2024

Background

Clinical Practice Research Datalink (CPRD) GOLD is an invaluable resource for clinical research. However, some exposures are difficult to capture, including continuous subcutaneous insulin infusion pump systems (“insulin pumps”). We present a strategy we developed to classify insulin pump users and to estimate the duration of pump use in CPRD GOLD. This was done to study adverse skin events in new adult pump users.

Methods

Insulin pump users were defined as patients who had a specific insulin pump code (prescription for an insulin pump cartridge or clinical code for continuous insulin infusion) in their record. Duration of use was defined as the continuous use of any insulin formulation commonly used in pump systems before and after the insulin pump specific code. Each patient’s pump start and end dates were calculated programmatically and then confirmed by manual review of the patient’s CPRD record.

Results

There were 1032 patients with an insulin pump specific code recorded in CPRD GOLD through December 2018, of which 302 met the inclusion criteria for our safety study. Due to high variability in the patterns of insulin use, programmatic determination of pump start and end dates was insufficient. The start and/or end dates of >50% of patients required adjustment upon manual review.

Conclusions

Insulin pump users in CPRD GOLD could be easily identified using this strategy, but we may have missed additional insulin pump users without specific pump codes. The duration of pump use, however, was difficult to capture. This strategy, though time intensive, is a useful tool for the study of insulin pumps.

Funding

This study was funded by AbbVie.

Conflicts of Interest Statement

Boston Collaborative Drug Surveillance Program (BCDSP) received funding from AbbVie for this study. Susan Jick and Rebecca Persson are employees of BCDSP. Todd Sponholtz and Brenda Baak were interns at BCDSP. Authors retain full and scientific control over the content of this manuscript.

Disclosures

This manuscript has not been peer-reviewed. We provide this information as a reference for other users of Clinical Practice Research Datalink GOLD.

This study is based in part on data from the Clinical Practice Research Datalink obtained under license from the UK Medicines and Healthcare products Regulatory Agency. The data is provided by patients and collected by the NHS as part of their care and support. The interpretation and conclusions contained in this study are those of the authors alone. This study was approved by the Independent Scientific Advisory Committee (ISAC) for Medicines and Healthcare products Regulatory Agency (protocol no: 19_216R).
Characteristics and Determinants of Pulmonary Long COVID
Authors: Patton Michael John , Benson Donald , Robison Sarah W. , Dhaval Raval , Locy Morgan L. , Patel Kinner , Grumley Scott , Levitan Emily B. , Morris Peter , Might Matthew , Gaggar Amit , Erdmann Nathaniel
Published: February 2024

RATIONALE

Persistent cough and dyspnea are prominent features of post-acute sequelae of SARS-CoV-2 (termed ’Long COVID’); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined.

OBJECTIVES

Using longitudinal pulmonary function testing (PFTs) and CT imaging, this study aimed to identify the characteristics and determinants of pulmonary Long COVID.

METHODS

The University of Alabama at Birmingham Pulmonary Long COVID cohort was utilized to characterize lung defects in patients with persistent pulmonary symptoms after resolution primary COVID infection. Longitudinal PFTs including total lung capacity (TLC) and diffusion limitation of carbon monoxide (DLCO) were used to evaluate restriction and diffusion impairment over time in this cohort. Analysis of chest CT imaging was used to phenotype the pulmonary Long COVID pathology. Risk factors linked to development of pulmonary Long COVID were estimated using univariate and multivariate logistic regression models.

MEASUREMENTS AND MAIN RESULTS

Longitudinal evaluation 929 patients with post-COVID pulmonary symptoms revealed diffusion impairment (DLCO ≤80%) and restriction (TLC ≤80%) in 51% of the cohort (n=479). In multivariable logistic regression analysis (adjusted odds ratio; aOR, 95% confidence interval [CI]), invasive mechanical ventilation during primary infection conferred the greatest increased odds of developing pulmonary Long COVID with diffusion impaired restriction (aOR=10.9 [4.09-28.6]). Finally, a sub-analysis of CT imaging identified evidence of fibrosis in this population.

CONCLUSIONS

Persistent diffusion impaired restriction was identified as a key feature of pulmonary Long COVID. Subsequent clinical trials should leverage combined symptomatic and quantitative PFT measurements for more targeted enrollment of pulmonary Long COVID patients.
Mitral annular plane systolic excursion to left atrial volume ratio – a strainless relation with left ventricular filling pressures
Authors: Lindow Thomas , Tureli Hande Oktay , Eklund Gustafsson Charlotte , Manna Daniel , Wieslander Björn , Lindqvist Per , Venkateshvaran Ashwin
Published: February 2024

Purpose

Left atrial reservoir strain (LASr) offers diagnostic and prognostic value in patients with heart failure. However, LASr may be technically challenging and is not available to all clinical echocardiographers. Since LASr is a consequence of left atrial (LA) stretch during apical descent of the mitral annulus, we hypothesized that a ratio between mitral annular plane systolic excursion (MAPSE) and LA volume (LAV) may offer similar diagnostic value as LASr. We aimed to investigate the relationship between MAPSE/LAV and LASr and evaluate the diagnostic performance of MAPSE/LAV to identify patients with elevated LV filling pressure.

Methods

MAPSE/LAV and LA strain measures were obtained in patients referred for echocardiography due to aortic stenosis, and in patients who had undergone clinically indicated right heart catheterization (RHC) with simultaneous echocardiography.

Results

In 93 patients with moderate aortic stenosis, MAPSE/LAV was moderately correlated with LASr (r=0.57) but was lower in patients with elevated compared to normal LV filling pressure by echocardiography (0.11 vs. 0.16 mm/mL, p<0.001). In 72 patients who had undergone RHC and simultaneous echocardiography, MAPSE/LAV and LASr correlated weakly with pulmonary artery wedge pressure (PAWP) (r=-0.44 and r=0.37). MAPSE/LAV was lower in patients with elevated (>15 mmHg) vs. normal PAWP (0.14 mm/mL vs. 0.27 mm/mL). Accuracy for detection of elevated PAWP was similar for MAPSE/LAV (area under the curve MAPSE/LAV: 0.75 [0.58–0.92] and LASr: 0.75 [0.57–0.90]).

Conclusions

Despite a moderate correlation with LASr, MAPSE/LAV provided similar diagnostic value as LASr regarding LV filling pressures as determined by echocardiography and RHC.
Chronic pharmacologic manipulation of dopamine transmission ameliorates metabolic disturbance in syndrome caused by mutated trappc9
Authors: Li Yan , Usman Muhammad , Sapp Ellen , Ke Yuting , Wang Zejian , Boudi Adel , DiFiglia Marian , Li Xueyi
Published: February 2024

Loss-of-function mutations of the gene encoding the trafficking protein particle complex subunit 9 (trappc9) cause intellectual disability and obesity by unknown mechanisms. Genome-wide analysis links trappc9 to non-alcoholic fatty liver disease (NAFLD). The abrogation of trappc9 in mice has been shown to alter the density of neurons containing dopamine receptor D2 (DRD2) and/or DRD1 in the striatum. Here, we report that trappc9 deficiency in mice resulted in disruption of systemic glucose homeostasis and onset of obesity and NAFLD, which were relieved upon chronic treatment combining DRD2 agonist quinpirole and DRD1 antagonist SCH23390. The homeostasis of systemic glucose in trappc9-deficient mice was restored upon administrating quinpirole alone. Transcriptomic and proteomic analyses revealed signs of impairments in neurotransmitter secretion in trappc9-deficient mice. Brain examinations showed that trappc9-deficient mice synthesized dopamine normally, but their dopamine-secreting neurons had a lower abundance of structures for releasing dopamine in the striatum. Our study suggests that trappc9 loss-of-function causes obesity and NAFLD by constraining dopamine transmission.
Chromatin structure andvar2csa– a tango in regulation ofvargene expression in the human malaria parasite,Plasmodium falciparum?
Authors: Lenz Todd , Zhang Xu , Chakraborty Abhijit , Ardakany Abbas Roayaei , Prudhomme Jacques , Ay Ferhat , Deitsch Kirk , Le Roch Karine G.
Published: February 2024

Over the last few decades, novel methods have been developed to study how chromosome positioning within the nucleus may play a role in gene regulation. Adaptation of these methods in the human malaria parasite,Plasmodium falciparum, has recently led to the discovery that the three-dimensional structure of chromatin within the nucleus may be critical in controlling expression of virulence genes (vargenes). Recent work has implicated an unusual, highly conservedvargene calledvar2csain contributing to coordinated transcriptional switching, however how this gene functions in this capacity is unknown. To further understand howvar2csainfluencesvargene switching, targeted DNA double-strand breaks (DSBs) within the sub-telomeric region of chromosome 12 were used to delete the gene and the surrounding chromosomal region. To characterize the changes in chromatin architecture stemming from this deletion and how these changes could affectvargene expression, we used a combination of RNA-seq, Chip-seq and Hi-C to pinpoint epigenetic and chromatin structural modifications in regions of differential gene expression. We observed a net gain of interactions in sub-telomeric regions and internalvargene regions followingvar2csaknockout, indicating an increase of tightly controlled heterochromatin structures. Our results suggest that disruption ofvar2csaresults not only in changes invargene transcriptional regulation but also a significant tightening of heterochromatin clusters thereby disrupting coordinated activation ofvargenes throughout the genome. Altogether our result confirms a strong link between thevar2csalocus, chromatin structure andvargene expression.

AUTHOR SUMMARY

Malaria remains one of the deadliest parasite-borne diseases, causing not only over a half million deaths annually, but also infecting hundreds of millions more.Plasmodium falciparum,the protozoan parasite that is responsible for the most virulent form of human malaria, is transmitted to humans by infected female mosquitoes during a blood meal. Due to a growing resistance to all existing antimalarials, there is a need to identify novel targets to design new antimalarial strategies. Our research builds on the growing body of evidence that supports the role of genome organization or chromatin structure within the nucleus in controlling the parasite development as well as virulence factors designed to circumvent the host immune response. This study identifies genes and structural elements within thePlasmodium falciparumgenome that are controlled, at least partially, by the expression of a single unique and highly conserved virulence gene.
Spatial top-down proteomics for the functional characterization of human kidney
Authors: Zemaitis Kevin J. , Fulcher James M. , Kumar Rashmi , Degnan David J. , Lewis Logan A. , Liao Yen-Chen , Veličković Marija , Williams Sarah M. , Moore Ronald J. , Bramer Lisa M. , Veličković Dušan , Zhu Ying , Zhou Mowei , Paša-Tolić Ljiljana
Published: February 2024

Background

The Human Proteome Project has credibly detected nearly 93% of the roughly 20,000 proteins which are predicted by the human genome. However, the proteome is enigmatic, where alterations in amino acid sequences from polymorphisms and alternative splicing, errors in translation, and post-translational modifications result in a proteome depth estimated at several million unique proteoforms. Recently mass spectrometry has been demonstrated in several landmark efforts mapping the human proteoform landscape in bulk analyses. Herein, we developed an integrated workflow for characterizing proteoforms from human tissue in a spatially resolved manner by coupling laser capture microdissection, nanoliter-scale sample preparation, and mass spectrometry imaging.

Results

Using healthy human kidney sections as the case study, we focused our analyses on the major functional tissue units including glomeruli, tubules, and medullary rays. After laser capture microdissection, these isolated functional tissue units were processed with microPOTS (microdroplet processing in one-pot for trace samples) for sensitive top-down proteomics measurement. This provided a quantitative database of 616 proteoforms that was further leveraged as a library for mass spectrometry imaging with near-cellular spatial resolution over the entire section. Notably, several mitochondrial proteoforms were found to be differentially abundant between glomeruli and convoluted tubules, and further spatial contextualization was provided by mass spectrometry imaging confirming unique differences identified by microPOTS, and further expanding the field-of-view for unique distributions such as enhanced abundance of a truncated form (1-74) of ubiquitin within cortical regions.

Conclusions

We developed an integrated workflow to directly identify proteoforms and reveal their spatial distributions. Where of the 20 differentially abundant proteoforms identified as discriminate between tubules and glomeruli by microPOTS, the vast majority of tubular proteoforms were of mitochondrial origin (8 of 10) where discriminate proteoforms in glomeruli were primarily hemoglobin subunits (9 of 10). These trends were also identified within ion images demonstrating spatially resolved characterization of proteoforms that has the potential to reshape discovery-based proteomics because the proteoforms are the ultimate effector of cellular functions. Applications of this technology have the potential to unravel etiology and pathophysiology of disease states, informing on biologically active proteoforms, which remodel the proteomic landscape in chronic and acute disorders.
Engineering multi-degrading bacterial communities to bioremediate soils contaminated with pesticides residues
Authors: Thieffry Sylvia , Aubert Julie , Devers-Lamrani Marion , Martin-Laurent Fabrice , Romdhane Sana , Rouard Nadine , Siol Mathieu , Spor Aymé
Published: February 2024

Parallel to the important use of pesticides in conventional agriculture there is a growing interest for green technologies to clear contaminated soil from pesticides and their degradation products. One specific technique, the inoculation of degrading micro-organisms in polluted soil, known as bioaugmentation, is a promising method still in needs of further developments. Specifically, improvements in the understanding of how degrading microorganisms must overcome abiotic filters and interact with the autochthonous microbial communities are needed in order to efficiently design bioremediation strategies. Here we designed a protocol aiming at studying the degradation of two herbicides, glyphosate (GLY) and isoproturon (IPU),viaexperimental modifications of two source bacterial communities. We used statistical methods stemming from genomic prediction to link community composition to herbicides degradation potentials. Our approach proved to be efficient with correlation estimates over 0.8 - between model predictions and measured pesticide degradation values. OTUs significantly associated with the degradation ability, and therefore identified as relevant by the models were confronted to the literature. Next, multi-degrading bacterial communities were obtained by coalescing bacterial communities with high GLY or IPU degradation ability based on their community-level properties. Finally, we evaluated the efficiency of constructed multi-degrading communities to remove pesticide contamination in a different soil. While results are less clear in the case of GLY, we showed an efficient transfer of degrading capacities towards the receiving soil even at relatively low inoculation levels in the case of IPU. Altogether, we developed an innovative protocol for building multi-degrading simplified bacterial communities with the help of genomic prediction tools and coalescence, and proved their efficiency in a contaminated soil.
FakA impacts antiseptic susceptibility inStaphylococcus aureusandEnterococcus faecalis
Authors: Gaya Maria Solsona , Felgate Heather , Siani Harsha , Whitchurch Cynthia B , Webber Mark A
Published: February 2024

Biocides are widely used to control and prevent healthcare-associated infections and understanding how nosocomial pathogens respond to biocidal agents is key to improving infection prevention and control products and practices.

An evolution model was used to study howStaphylococcus aureusandEnterococcus faecalisresponded after repeated exposure to sub-lethal concentrations of chlorhexidine digluconate (CHX) and octenidine dihydrochloride (OCT) when grown planktonically and as biofilms.

Both pathogens were able to adapt to grow at concentrations above the MIC of both biocides with planktonic lineages surviving at higher concentrations of both agents than biofilm lineages. Exposure to CHX was linked with lower biofilm biomass production inE. faecalisalthough biofilm biomass increased forS. aureusisolates after exposure to both agents. Evolved isolates had no major fitness deficit and only low-level changes to susceptibility to antibiotics were observed after biocide exposure.

Sequencing of biocide adapted mutants repeatedly identified mutations withinfakAencoding a fatty acid kinase in independent lineages ofS. aureusafter exposure to both biocides in all conditions. Analogous changes were observed within the homologous gene in parallel experiments withEnterococcus faecalis. Further assays to study the mechanistic basis and relationship to phospholipid production showed that evolved isolates withfakAmutations accumulated less ethidium bromide than parent strains, exhibited altered cell envelope morphology and decreased susceptibility to daptomycin.

This data shows important pathogens can evolve limited tolerance to two common biocides but that this has collateral impacts on biofilm formation, colony morphology and fitness. FakA appears to play an important role in biocide tolerance.
The N-terminal helix of MarA as a key element in the mechanism of DNA binding
Authors: Corbella Marina , Moreira Cátia , Bello-Madruga Roberto , Torrent Marc , Kamerlin Shina C.L. , Blair Jessica M.A. , Sancho-Vaello Enea
Published: February 2024

Efflux is one of the mechanisms employed by Gram-negative bacteria to become resistant to routinely used antibiotics. The inhibition of efflux by targeting their regulators is a promising strategy to re-sensitise bacterial pathogens to antibiotics. AcrAB-TolC is the main Resistance-Nodulation-Division efflux pump in Enterobacteriaceae. MarA is an AraC/XylS family global regulator that regulates more than 40 genes related to the antimicrobial resistance phenotype, includingacrAB. The aim of this work was to understand the role of the N-terminal helix of MarA in the mechanism of DNA binding. An N-terminal deletion of MarA showed that the N-terminal helix has a role in the recognition of the functional marboxes. By engineering two double cysteine variants of MarA, and combiningin vitroelectrophoretic mobility assays andin vivomeasurements ofacrABtranscription with molecular dynamic simulations, it was shown that the immobilization of the N-terminal helix of MarA prevents binding to DNA. This new mechanism of inhibition seems to be universal for the monomeric members of the AraC/XylS family, as suggested by additional molecular dynamics simulations of the two-domain protein Rob. These results point to the N-terminal helix of the AraC/XylS family monomeric regulators as a promising target for the development of inhibitors.
Neural codes track prior events in a narrative and predict subsequent memory for details
Authors: Collin Silvy H.P. , Kempner Ross P. , Srivatsan Sunita , Norman Kenneth A.
Published: February 2024

Abstract

Throughout our lives, we learn schemas that specify what types of events to expect in particular contexts and the temporal order in which these events usu- ally occur. Here, our first goal was to investigate how such context-dependent temporal structures are represented in the brain during processing of temporally- extended events. To accomplish this, we ran a 2-day fMRI study in which we exposed participants to many unique animated videos of weddings composed of sequences of rituals; each sequence originated from one of two fictional cultures (North and South), where rituals were shared across cultures, but the transition structure between these rituals differed across cultures. The results, obtained using representational similarity analysis, revealed that context-dependent tem- poral structure is represented in multiple ways in parallel, including distinct neural representations for the culture, for particular sequences, and for past and current events within the sequence. Our second goal was to test the hypothe- sis that neural schema representations scaffold memory for specific details. In keeping with this hypothesis, we found that the strength of the neural represen- tation of the North/South schema for a particular wedding predicted subsequent episodic memory for the details of that wedding.
Applying an automated NMR-based metabolomic workflow to unveil strawberry molecular mechanisms in vernalization
Authors: Fernández-Veloso Andrea , Hiniesta-Valero Jaime , Guerra-Castellano Alejandra , Tomás Laura , De la Rosa Miguel A. , Díaz-Moreno Irene
Published: February 2024

Metabolomics is the discipline that aims to determine the whole metabolic profile of a complex mixture. These studies are useful to capture the physiological status of an organism at a given moment. Even though the main technique used in metabolomics is Mass Spectrometry coupled to chromatography, in recent years, interest in Nuclear Magnetic Resonance (NMR) is increasing because of some benefits of NMR, i.e., it is a non-invasive, highly reproducible, and inherently quantitative technique. However, difficulties in data analysis comprise one of the main reasons that hinder the standardization of NMR for metabolomic analysis in research. In this work, we applied an automated workflow for NMR-based metabolomic analysis for the study of vernalization in strawberry. Vernalization is a key process in obtaining a successful strawberry crop, however, the molecular mechanisms behind it remain still unknown. We expect this work to improve the knowledge of crop metabolism —specifically the vernalization process— while promoting the use of NMR in conjunction with computational tools for agriculture studies.
In Vitro/In VivoAssessment of Aripiprazole-Loaded Thiolated Arabinoxylan based Nanoparticles: An Innovative Approach for Targeted Schizophrenia Therapy
Authors: Sikander Mehwish , Tulain Ume Ruqia , Malik Nadia Shamshad , Mahmood Arshad , Erum Alia , Khan Muhammad Tariq , Safdar Asif
Published: February 2024

This study was conducted with the primary objective of improving the bioavailability of aripiprazole (APZ) through the development of nanoparticles using thiolated arabinoxylan (TAX) sourced from corn husk. TAX was synthesized via thiolation, employing thiourea as a thiol donor and hydrochloric acid as a catalyst. Characterization of TAX revealed a surface free thiol group content of 37.461 mmol/g, accompanied by an angle of repose measuring 0.393±0.035. Bulk density, tapped density, Hausner ratio, and Carr index fell within prescribed limits. Subsequently, APZ-loaded thiolated arabinoxylan based nanoparticles were fabricated using the ionotropic gelation method, with barium chloride serving as a cross-linker. Encapsulation efficiency was highest for formulation F4, at 97.1%±2.36. In vitro drug release demonstrated sustained release profiles at both pH 1.2 and pH 6.8, with F4 exhibiting the most favourable release kinetics. In vitro, characterization indicated that the optimized thiolated arabinoxylan based nanoparticle formulation had an average particle size of 211.1 nm with a Polydispersity Index (PDI) of 0.092 and a zeta potential of 0.621 mV. SEM imaging showed uniform, slightly spherical particles with minimal pores. DSC and TGA confirmed the conversion of APZ to amorphous states within the nanoparticles, enhancing solubility. Ex-vivo permeation studies exhibited favourable drug permeation. An In-vivo pharmacodynamics studies in a ketamine-induced schizophrenia rat model indicated the effectiveness of APZ loaded thiolated arabinoxylan based nanoparticles in behavioural tests, with no significant cataplectic effects observed. Acute oral toxicity assessments demonstrated the safety, with no mortality, no significant alterations in food and water consumption, or any histopathological abnormalities. In conclusion, these developed APZ-loaded thiolated arabinoxylan based nanoparticles hold promise for the effective treatment of schizophrenia without inducing toxic effects, showcasing their potential for clinical applications.
In-host evolution of classic to convergentKlebsiella pneumoniaesequence type 147 isolates and impact of associated capsular changes on different morphotypes
Authors: Sydow Katharina , Doğan Eyüp , Schwabe Michael , Heiden Stefan E. , Khan Muhammad Moman , Müller Justus U. , Bohnert Jürgen A. , Baecker Daniel , Schlüter Rabea , Schierack Peter , Eger Elias , Idelevich Evgeny A. , Becker Karsten , Schaufler Katharina
Published: February 2024

Klebsiella pneumoniae, an important opportunistic pathogen, has long been categorized into two distinct pathotypes: the often multidrug-resistant classic (cKp) and the highly virulent hypervirulent (hvKp). However, a recent global trend has witnessed the emergence of convergent strains, seamlessly combining antimicrobial resistance with hypervirulence. Our study delved into a series ofK. pneumoniaeisolates sourced from the same patient, all belonging to the international, high-risk clonal lineage of sequence type 147. As reported in a previous study, these isolates exhibited diverse morphotypes on blood agar, ranging from small white to normal-sized white, grey, or grey and dry (g/d) colonies.

Through an interplay of omics and phenotypic experiments, we unraveled the intricate mechanisms governing these distinct colony morphologies and their implications on bacterial virulence and resilience. While the earlier isolates demonstrated modest levels of resistance and virulence, their later counterparts showed significantly heightened levels, attributed to the acquisition of additional plasmids. Bioinformatics analysis unveiled a chromosomal insertion of a hybrid plasmid in one isolate, marking an unprecedented in-host microevolution from the classic to the convergent pathotype.

All morphotypes exhibited positive insertion sequences around or within the K loci, with the grey or g/d phenotypes arising from impaired K loci. Despite lower serum resistance, these morphotypes demonstrated superior adhesion to human epithelial cells. Interestingly, while capsule-deficient strains are conventionally associated with decreased virulence, our isolates displayed high mortality rates in theGalleria mellonellainfection model.

In conclusion, our findings not only provide unprecedented insights into in-host microevolution within a patient, transitioning from the classic to the convergent pathotype, but also contribute significantly to the understanding of the diverse morphotypes exhibited byK. pneumoniae.
Lineage-specific intersection of endothelin and GDNF signaling in enteric nervous system development
Authors: Poltavski Denise M. , Cunha Alexander T. , Tan Jaime , Sucov Henry M. , Makita Takako
Published: February 2024

Two major ligand-receptor signaling axes – endothelin Edn3 and its receptor Ednrb, and glial-derived neurotrophic factor (GDNF) and its receptor Ret – are required for migration of enteric nervous system (ENS) progenitors to the hindgut. Mutations in either component cause colonic aganglionosis, also called Hirschsprung disease. Here, we have used Wnt1Cre and Pax2Cre in mice to show that these driver lines label distinct ENS lineages during progenitor migration and in their terminal hindgut fates. Both Cre lines result in Hirschsprung disease when combined with conditionalEdnrbor conditionalRetalleles. In vitro explant assays and analysis of lineage-labeled mutant embryos show that GDNF but not Edn3 is a migration cue for cells of both lineages. Instead, Edn3-Ednrb function is required in both for GDNF responsiveness albeit in different ways: by expanding the Ret+population in the Pax2Cre lineage, and by supporting Ret function in Wnt1Cre-derived cells. Our results demonstrate that two distinct lineages of progenitors give rise to the ENS, and that these divergently utilize endothelin signaling to support migration to the hindgut.
Detection, isolation and characterisation of phage-host complexes using BONCAT and click chemistry
Authors: Hellwig P. , Dittrich A. , Heyer R. , Reichl U. , Benndorf D.
Published: February 2024

Phages are viruses that infect prokaryotes and can shape microbial communities by lysis, thus offering applications in various fields. However, challenges exist in sampling, isolation, and predicting host specificity of phages. A new workflow using biorthogonal non-canonical amino acid tagging (BONCAT) and click chemistry (CC) allows combined analysis of phages and their hosts.

Replication of phage λ inEscherichia coliwas selected as a model for workflow development. Specific labelling of phage λ proteins with the non-canonical amino acid 4-azido-L-homoalanine (AHA) during infection ofE. coliwas confirmed by LC-MS/MS. Subsequent tagging of AHA with fluorescent dyes via CC allowed the visualization of phages adsorbed to the cell surface by fluorescence microscopy. Flow cytometry enabled the automated detection of these fluorescent phage-host complexes. AHA-labeled phages were tagged with biotin for purification by affinity chromatography. The biotinylated phages could be purified and were infectious despite biotinylation after purification. Applying this assay approach to environmental samples would enable host screening without cultivation.

A flexible and powerful workflow was established to detect and enrich phages and their hosts. In the future, fluorescence-activated cell sorting or biotin purification could be used to isolate phage-host complexes in microbial communities.
Parsing Brain Network Specialization: A Replication and Expansion of Wang et al. (2014)
Authors: Peterson Madeline , Floris Dorothea L. , Nielsen Jared A.
Published: February 2024

One organizing principle of the human brain is hemispheric specialization, or the dominance of a specific function or cognitive process in one hemisphere or the other. Previously, Wang et al. (2014) identified networks putatively associated with language and attention as being specialized to the left and right hemispheres, respectively; and a dual-specialization of the executive control network. However, it remains unknown which networks are specialized when specialization is examined within individuals using a higher resolution parcellation, as well as which connections are contributing the most to a given network’s specialization. In the present study, we estimated network specialization across three datasets using the autonomy index and a novel method of deconstructing network specialization. After examining the reliability of these methods as implemented on an individual level, we addressed two hypotheses. First, we hypothesized that the most specialized networks would include those associated with language, visuospatial attention, and executive control. Second, we hypothesized that within-network contributions to specialization would follow a within-between network gradient or a specialization gradient. We found that the majority of networks exhibited greater within-hemisphere connectivity than between-hemisphere connectivity. Among the most specialized networks were networks associated with language, attention, and executive control. Additionally, we found that the greatest network contributions were within-network, followed by those from specialized networks.

Significance Statement

Hemispheric specialization is a characteristic of brain organization that describes when a function draws on one hemisphere of the brain more than the other. We sought to identify the most specialized brain networks within individuals, as well as which connections contribute the most to a given network’s specialization. Among the most specialized networks were those associated with language, attention, and executive control. Unexpectedly, we also identified networks associated with emotion/memory and theory of mind as highly specialized. Additionally, we found support for guiding principles of brain organization generally, such that within-network connections contributed most to a given network’s specialization followed by connections from other specialized networks. These results have implications for identifying potential variations of network contributions in individuals with neurodevelopmental conditions.
Ramping cells in rodent mPFC encode time to past and future events via real Laplace transform
Authors: Cao Rui , Bright Ian M. , Howard Marc W.
Published: February 2024

In interval reproduction tasks, animals must remember the event starting the interval and anticipate the time of the planned response to terminate the interval. The interval reproduction task thus allows for studying both memory for the past and anticipation of the future. We analyzed previously published recordings from rodent mPFC (Henke et al., 2021) during an interval reproduction task and identified two cell groups by modeling their temporal receptive fields using hierarchical Bayesian models. The firing in the “past cells” group peaked at the start of the interval and relaxed exponentially back to baseline. The firing in the “future cells” group increased exponentially and peaked right before the planned action at the end of the interval. Contrary to the previous assumption that timing information in the brain has one or two time scales for a given interval, we found strong evidence for a continuous distribution of the exponential rate constants for both past and future cell populations. The real Laplace transformation of time predicts exponential firing with a continuous distribution of rate constants across the population. Therefore, the firing pattern of the past cells can be identified with the Laplace transform of time since the past event while the firing pattern of the future cells can be identified with the Laplace transform of time until the planned future event.
Characterizing directional dynamics of semantic prediction based on inter-regional temporal generalization
Authors: Mamashli Fahimeh , Khan Sheraz , Hatamimajoumerd Elaheh , Jas Mainak , Uluç Işıl , Lankinen Kaisu , Obleser Jonas , Friederici Angela D. , Maess Burkhard , Ahveninen Jyrki
Published: February 2024

The event-related potential/field component N400(m) has been widely used as a neural index for semantic prediction. It has long been hypothesized that feedback information from inferior frontal areas plays a critical role in generating the N400. However, due to limitations in causal connectivity estimation, direct testing of this hypothesis has remained difficult. Here, magnetoencephalography (MEG) data was obtained during a classic N400 paradigm where the semantic predictability of a fixed target noun was manipulated in simple German sentences. To estimate causality, we implemented a novel approach based on machine learning and temporal generalization to estimate the effect of inferior frontal gyrus (IFG) on temporal areas. In this method, a support vector machine (SVM) classifier is trained on each time point of the neural activity in IFG to classify less predicted (LP) and highly predicted (HP) nouns and then tested on all time points of superior/middle temporal sub- regions activity (and vice versa, to establish spatio-temporal evidence for or against causality). The decoding accuracy was significantly above chance level when the classifier was trained on IFG activity and tested on future activity in superior and middle temporal gyrus (STG/MTG). The results present new evidence for a model predictive speech comprehension where predictive IFG activity is fed back to shape subsequent activity in STG/MTG, implying a feedback mechanism in N400 generation. In combination with the also observed strong feedforward effect from left STG/MTG to IFG, our findings provide evidence of dynamic feedback and feedforward influences between IFG and temporal areas during N400 generation.
Different subregions of monkey lateral prefrontal cortex respond to abstract sequences and their components
Authors: Rodriguez Nadira Yusif , Ahuja Aarit , Basu Debaleena , McKim Theresa H. , Desrochers Theresa M.
Published: February 2024

Sequential information permeates daily activities, such as when watching for the correct series of buildings to determine when to get off the bus or train. These sequences include periodicity (the spacing of the buildings), the identity of the stimuli (the kind of house), and higher-order more abstract rules that may not depend on the exact stimulus (e.g. house, house, house, business).

Previously, we found that the posterior fundus of area 46 in the monkey lateral prefrontal cortex (LPFC) responds to rule changes in such abstract visual sequences. However, it is unknown if this region responds to other components of the sequence, i.e., image periodicity and identity, in isolation. Further, it is unknown if this region dissociates from other, more ventral LPFC subregions that have been associated with sequences and their components. To address these questions, we used awake functional magnetic resonance imaging in three male macaque monkeys during two no-report visual tasks. One task contained abstract visual sequences, and the other contained no visual sequences but maintained the same image periodicity and identities.

We found the fundus of area 46 responded only to abstract sequence rule violations. In contrast, the ventral bank of area 46 responded to changes in image periodicity and identity, but not changes in the abstract sequence. These results suggest a functional specialization within anatomical substructures of LPFC to signal different kinds of stimulus regularities. This specialization may provide key scaffolding to identify abstract patterns and construct complex models of the world for daily living.

Significance Statement

Daily tasks, such as a bus commute, require tracking or monitoring your place (same, same, same, different building) until your stop. Sequence components such as rule, periodicity (timing), and item identity are involved in this process. While prior work located responses to sequence rule changes to area 46 of monkey lateral prefrontal cortex (LPFC) using awake monkey fMRI, less was known about other components. We found that LPFC subregions differentiated between sequence components. Area 46 posterior fundus responded to abstract visual sequence rule changes, but not to changes in image periodicity or identity. The converse was true for the more ventral, adjacent shoulder region. These results suggest that interactions between adjacent LPFC subregions provide key scaffolding for complex daily behaviors.
Focused Ultrasound Modulates Dopamine in a Mesolimbic Reward Circuit
Authors: Olaitan Greatness O. , Ganesana Mallikarjunarao , Strohman Andrew , Lynch Wendy J. , Legon Wynn , Jill Venton B.
Published: February 2024

Dopamine is a neurotransmitter that plays a significant role in reward and motivation. Dysfunction in the mesolimbic dopamine pathway has been linked to a variety of psychiatric disorders, including addiction. Low-intensity focused ultrasound (LIFU) has demonstrated effects on brain activity, but how LIFU affects dopamine neurotransmission is not known. Here, we applied three different intensities (6.5, 13, and 26 W/cm2Isppa) of 2-minute LIFU to the prelimbic region (PLC) and measured dopamine in the nucleus accumbens (NAc) core using fast-scan cyclic voltammetry. Two minutes of LIFU sonication at 13 W/cm2to the PLC significantly reduced dopamine release by ∼ 50% for up to 2 hours. However, double the intensity (26 W/cm2) resulted in less inhibition (∼30%), and half the intensity (6.5 W/cm2) did not result in any inhibition of dopamine. Anatomical controls applying LIFU to the primary somatosensory cortex did not change NAc core dopamine, and applying LIFU to the PLC did not affect dopamine release in the caudate or NAc shell. Histological evaluations showed no evidence of cell damage or death. Modeling of temperature rise demonstrates a maximum temperature change of 0.5°C with 13 W/cm2, suggesting that modulation is not due to thermal mechanisms. These studies show that LIFU at a moderate intensity provides a noninvasive, high spatial resolution means to modulate specific mesolimbic circuits that could be used in future studies to target and repair pathways that are dysfunctional in addiction and other psychiatric diseases.
Cost-benefit Tradeoff Mediates the Rule- to Memory-based Processing Transition during Practice
Authors: Yang Guochun , Jiang Jiefeng
Published: February 2024

Practice not only improves task performance but also changes task execution from rule-to memory-based processing by incorporating experiences from practice. However,howandwhenthis change occurs is unclear. We test the hypothesis that strategy transitions in task learning can result from decision-making guided by cost-benefit analysis. Participants learn two task sequences and are then queried about the task type at a cued sequence and position. Behavioral improvement with practice can be accounted for by a computational model implementing cost-benefit analysis, and the model-predicted strategy transition points align with the observed behavioral slowing. Model comparisons using behavioral data show that strategy transitions are better explained by a cost-benefit analysis across alternative strategies rather than solely on memory strength. Model-guided fMRI findings suggest that the brain encodes a decision variable reflecting the cost-benefit analysis and that different strategy representations are double-dissociated. Further analyses reveal that strategy transitions are associated with activation patterns in the dorsolateral prefrontal cortex and increased pattern separation in the ventromedial prefrontal cortex. Together, these findings support cost-benefit analysis as a mechanism of practice-induced strategy shift.