bluuebunny/crossref_metadata_2025 huggingface dataset:
Projection-specific integration of convergent thalamic and retrosplenial signals in the presubicular head direction cortex
Authors: Richevaux Louis , Lim Dongkyun , Nassar Mérie , Rodrigues Léa Dias , Mauthe Constanze , Cohen Ivan , Sol-Foulon Nathalie , Fricker Desdemona
Published: March 2023

Head-direction (HD) signals function as the brain’s internal compass. They are organized as an attractor, and anchor to the environment via visual landmarks. Here we examine how thalamic HD signals and visual landmark information from the retrosplenial cortex combine in the presubiculum. We find that monosynaptic excitatory connections from anterior thalamic nucleus and from retrosplenial cortex converge on single layer 3 pyramidal neurons in the dorsal portion of mouse presubiculum. Independent dual wavelength photostimulation of these inputs in slices leads to action potential generation preferentially for near-coincident inputs, indicating that layer 3 neurons can transmit a visually matched HD signal to medial entorhinal cortex. Layer 4 neurons, which innervate the lateral mammillary nucleus, form a second step in the association of HD and landmark signals. They receive little direct input from thalamic and retrosplenial axons. We show that layer 4 cells are excited di-synaptically, transforming regular spiking activity into bursts of action potentials, and that their firing is enhanced by cholinergic agonists. Thus, a coherent sense of orientation involves projection specific translaminar processing in the presubiculum, where neuromodulation facilitates landmark updating of HD signals in the lateral mammillary nucleus.
Actomyosin pulsing rescues embryonic tissue folding from disruption by myosin fluctuations
Authors: Zhu Hongkang , O’Shaughnessy Ben
Published: March 2023

During early development, myosin II mechanically reshapes and folds embryo tissue. A much-studied example is ventral furrow formation inDrosophila, marking the onset of gastrulation. Furrowing is driven by contraction of actomyosin networks on apical cell surfaces, but how the myosin patterning encodes tissue shape is unclear, and elastic models failed to reproduce essential features of experimental cell contraction profiles. The myosin patterning exhibits substantial cell-to-cell fluctuations with pulsatile time-dependence, a striking but unexplained feature of morphogenesis in many organisms. Here, using biophysical modeling we find viscous forces offer the principle resistance to actomyosin-driven apical constriction. In consequence, tissue shape is encoded in the direction-dependent curvature of the myosin patterning which orients an anterior-posterior furrow. Tissue contraction is highly sensitive to cell-to-cell myosin fluctuations, explaining furrowing failure in genetically perturbed embryos whose fluctuations are temporally persistent. In wild-type embryos, this catastrophic outcome is averted by pulsatile myosin time-dependence, a time-averaging effect that rescues furrowing. This low pass filter mechanism may underlie the usage of actomyosin pulsing in diverse morphogenetic processes across many organisms.
Interferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15
Authors: Biswas Uddipta , Moro Ramona N. , Kharat Suhas S. , Das Prosun , Chaudhuri Arnab Ray , Sharan Shyam K. , Penengo Lorenza
Published: March 2023

DNA replication and repair defects or genotoxic treatments trigger interferon (IFN)-mediated inflammatory responses. However, whether and how IFN signaling in turn impacts the DNA replication process has remained elusive. Here we show that IFN promotes replication fork stability, cell proliferation and survival in BRCA1/2-defective cancer cells and rescues the lethality of BRCA2-deficient mouse embryonic stem cells. Although IFN activates hundreds of genes, these effects are specifically mediated by the ubiquitin-like modifier ISG15 (IFN-stimulated gene 15). Inactivation of ISG15 or of the enzymes promoting its conjugation, referred as ISGylation, completely suppresses the impact of IFN on the replication process. Depletion of ISG15 significantly reduces cell proliferation rates whereas its upregulation results in increased resistance to the chemotherapeutic drug cisplatin in human BRCA1-mutated triple-negative and mouse BRCA2-deficient breast cancer cells, respectively. Accordingly, cells carrying BRCA1/2 defects consistently show increased ISG15 levels, representing a novel, in-built mechanism of drug resistance linked to BRCAness.
SYNTHETIC CIRCUITS BASED ON SPLIT CAS9 TO DETECT CELLULAR EVENTS
Authors: Przybyszewska-Podstawka Alicja , Czapinski Jakub , Kalafut Joanna , Rivero-Muller Adolfo
Published: March 2023

Synthetic biology involves the generation of logic circuits to create or control biological functions and behaviours by engineering interconnected genetic elements such as promoters, repressors, and transcriptional activators. CRISPR discovery, and its adaptations to mammalian cells, has made it the tool of choice in molecular biology and revolutionized genome engineering in biomedical sciences. Here, we describe an adaptation of a split Cas9 to generate synthetic logic gates to sense biological events. As proof-of-concept, the complementing halves of split Cas9 were placed under different promoters, one unique to cancer cells of epithelial origin (phCEA) and one universal promoter (pCMV). We used self-assembling inteins to reunite the halves when co-expressed. Only cancer cells with epithelial origin expressed both halves and activated a reporter becoming green fluorescent. We then investigated whether we could apply this system to the detection of biological processes such as epithelial to mesenchymal transition (EMT). We designed another logic gate where one halve is expressed only by cancer cells of epithelial origin, while the other is activated during EMT - under the control of TWIST1. Indeed, cells undergoing EMT were detected by the activation of the reporter. Finally, the split-Cas9 logic gate was applied as a sensor to detect cell-cell fusion events in multiple cell lines. Each cell type expressed only one halve of split Cas9, and only induction of fusion resulted in the appearance of multinucleated syncytia and the expression of the reporter system. The simplicity and flexibility of the split Cas9 system reported here can be integrated to many other cellular processes, not only as a sensor but as an actuator.
Transcription regulation by CarD in mycobacteria is guided by basal promoter kinetics
Authors: Zhu Dennis X. , Stallings Christina L.
Published: March 2023

Bacterial pathogens likeMycobacterium tuberculosis(Mtb) employ transcription factors to adapt their physiology to the diverse environments within their host. CarD is a conserved bacterial transcription factor that is essential for viability inMtb. Unlike classical transcription factors that recognize promoters by binding to specific DNA sequence motifs, CarD binds directly to the RNA polymerase (RNAP) to stabilize the open complex intermediate (RPo) during transcription initiation. We previously showed using RNA-sequencing that CarD is capable of both activating and repressing transcriptionin vivo. However, it is unknown how CarD achieves promoter specific regulatory outcomes inMtbdespite binding indiscriminate of DNA sequence. We propose a model where CarD’s regulatory outcome depends on the promoter’s basal RPostability and test this model usingin vitrotranscription from a panel of promoters with varying levels of RPostability. We show that CarD directly activates full-length transcript production from theMtbribosomal RNA promoterrrnAP3 (AP3) and that the degree of transcription activation by CarD is negatively correlated with RPostability. Using targeted mutations in the extended −10 and discriminator region of AP3, we show that CarD directly represses transcription from promoters that form relatively stable RPo. DNA supercoiling also influenced RPostability and affected the direction of CarD regulation, indicating that the outcome of CarD activity can be regulated by factors beyond promoter sequence. Our results provide experimental evidence for how RNAP-binding transcription factors like CarD can exert specific regulatory outcomes based on the kinetic properties of a promoter.
Polygenic pathogen networks control of host and pathogen transcriptional plasticity in the Arabidopsis-Botrytis pathosystem
Authors: Krishnan Parvathy , Caseys Celine , Soltis Nik , Zhang Wei , Burow Meike , Kliebenstein Daniel J.
Published: March 2023

Bidirectional flow of information shapes the outcome of the host-pathogen interactions and depends on the genetics of each organism. Recent work has begun to use co-transcriptomic studies to shed light on this bidirectional flow, but it is unclear how plastic the co-transcriptome is in response to genetic variation in both the host and pathogen. To study co-transcriptome plasticity, we conducted transcriptomics using natural genetic variation in the pathogen, Botrytis cinerea, and large effect genetic variation abolishing defense signaling pathways within the host, Arabidopsis thaliana. We show that genetic variation in the pathogen has a greater influence on the co-transcriptome than mutations that abolish defense signaling pathways in the host. Genome wide association mapping using the pathogens genetic variation and both organisms’ transcriptomes allowed an assessment of how the pathogen modulates plasticity in response to the host. This showed that the differences in both organism’s responses were linked to trans-eQTL hotspots within the pathogen’s genome. These hotspots control gene sets in either the host or pathogen and show differential allele sensitivity to the hosts genetic variation rather than qualitative host specificity. Interestingly, nearly all the trans-eQTL hotspots were unique to the host or pathogen transcriptomes. In this system of differential plasticity, the pathogen mediates the shift in the co-transcriptome more than the host.
Cell cycle perturbation uncouples mitotic progression and invasive behavior in a post-mitotic cell
Authors: Martinez Michael A. Q. , Zhao Chris Z. , Moore Frances E. Q. , Yee Callista , Zhang Wan , Shen Kang , Martin Benjamin L. , Matus David Q.
Published: March 2023

The acquisition of the post-mitotic state is crucial for the execution of many terminally differentiated cell behaviors during organismal development. However, the mechanisms that maintain the post-mitotic state in this context remain poorly understood. To gain insight into these mechanisms, we used the genetically and visually accessible model ofC. elegansanchor cell (AC) invasion into the vulval epithelium. The AC is a terminally differentiated uterine cell that normally exits the cell cycle and enters a post-mitotic state, initiating contact between the uterus and vulva through a cell invasion event. Here, we set out to identify the set of negative cell cycle regulators that maintain the AC in this post-mitotic, invasive state. Our findings revealed a critical role for CKI-1 (p21CIP1/p27KIP1) in redundantly maintaining the post-mitotic state of the AC, as loss of CKI-1 in combination with other negative cell cycle regulators—including CKI-2 (p21CIP1/p27KIP1), LIN-35 (pRb/p107/p130), FZR-1 (Cdh1/Hct1), and LIN-23 (β-TrCP)—resulted in proliferating ACs. Remarkably, time-lapse imaging revealed that these ACs retain their ability to invade. Upon examination of a node in the gene regulatory network controlling AC invasion, we determined that proliferating, invasive ACs do so by maintaining aspects of pro-invasive gene expression. We therefore report that the requirement for a post-mitotic state for invasive cell behavior can be bypassed following direct cell cycle perturbation.
Perceived timing of postural instability onset
Authors: McIlroy Robert E , Barnett-Cowan Michael
Published: March 2023

Background

This study examines the perceived timing of postural instability onset, a crucial aspect of balance. Previous research using Temporal Order Judgment (TOJ) tasks found that postural perturbations need to occur significantly earlier than an auditory reference stimulus for individuals to perceive them as simultaneous. However, there are methodological concerns with this prior work, specifically regarding an unbalanced stimulus onset asynchrony (SOA) distribution.

Research question

Does the point of subjective simultaneity (PSS) between postural perturbation onset and an auditory reference stimulus differ for equal versus unequal SOA distributions?

Methods

A repeated measures design was utilized, presenting two different SOA distributions to 10 participants using a TOJ task during both the equal (72 trials) and unequal (88 trials) SOA distributions. Paired t-tests were used to determine if there was a significant difference between the PSS of the equal and unequal SOA distributions. Additionally, one-sample t-tests were performed on the PSS values of both the equal and unequal SOA distributions in comparison to 0ms (defined as true simultaneity) to determine if perceptual responses were delayed.

Results

The results indicate that the unequal SOA distribution resulted in a perceived delay of postural instability onset by 20.34ms, while the equal SOA distribution resulted in a perceived delay of the auditory stimulus of 3.52ms. However, neither condition was significantly different from each other nor from true simultaneity.

Significance

These findings suggest that the perception of postural instability onset is not slow, as previously thought, and highlight the importance of controlling methodological parameters when investigating sensory cues. This knowledge highlights the importance of controlling methodological parameters when investigating the perception of sensory cues and will help inform falls prevention strategies.
Retinotopic connectivity maps of human visual cortex with unconstrained eye movements
Authors: Tangtartharakul Gene T. , Morgan Catherine A. , Rushton Simon K. , Schwarzkopf D. Samuel
Published: March 2023

Human visual cortex contains topographic visual field maps whose organization can be revealed with retinotopic mapping. Unfortunately, constraints posed by standard mapping hinders its use in patients, atypical subject groups, and individuals at either end of the lifespan. This severely limits the conclusions we can draw about visual processing in such individuals. Here we present a novel data-driven method to estimate connective fields, fine-grained maps of the functional connectivity between brain areas. We find that inhibitory connectivity fields accompany, and often surround, facilitatory fields. The visual field extent of these inhibitory subfields falls off with cortical magnification. We further show that our method is robust to large eye movements and myopic defocus. Importantly, freed from the controlled stimulus conditions in standard mapping experiments, using entertaining stimuli and unconstrained eye movements our approach can generate retinotopic maps, including the periphery visual field hitherto only possible to map with special stimulus displays. Generally, our results show that the connective field method can gain knowledge about retinotopic architecture of visual cortex in patients and participants where this is at best difficult and confounded, if not impossible, with current methods.
Polymer brush inspired by ribosomal RNA transcription
Authors: Yamamoto Tetsuya , Li Wei
Published: March 2023

Pre-ribosomal RNAs are synthesized during the transcription by RNA polymerase I molecules localized at the surfaces of a nucleolus subcompartment. Inspired by the ribosomal RNA transcription, we here develop a scaling theory of a brush of polymers, where monomers are added to their grafted ends in the steady state. Our theory predicts that monomers newly added to the polymers stay at the vicinity of the surface due to the slow dynamics of the polymers and thus the polymer volume fraction increases with increasing the polymerization rate. The excluded volume interaction between polymers and reactant monomers suppresses the diffusion of reactant monomers and thus decreases the polymerization rate. The extent of the suppression of monomer diffusion increases with increasing the polymerization rate because the diffusion length decreases, rather than the condensation of polymers due to their slow dynamics.
Over-eruption in marsupial carnivore teeth: compensation for a constraint
Authors: Jones Menna E.
Published: March 2023

Pronounced over-eruption of the canine teeth, much greater than in eco-morphologically equivalent placental carnivores, occurs with age and growth in Australian marsupial carnivores. Suppression of functional tooth replacement is a characteristic of marsupials and is frequent among diverse placentals, where the primitive therian pattern is two generations of incisor, canine and premolar teeth. Rapid determinate growth is one among multiple hypotheses proposed to explain the loss of tooth replacement in mammals. In this line of reasoning, the animal reaches a sufficient body or jaw size to accommodate adult-sized teeth by the time it requires functional dentition. Marsupial carnivores have a full set of adult anterior teeth at weaning, which erupt into a juvenile jaw that is 25 to 30 % adult size, compared with well grown in placental carnivores. Indeterminate over-eruption of the canine teeth in marsupial carnivores results in increasing canine height and diameter with increasing body size with age, suggesting this is a compensatory mechanism for the constraint of a single generation of anterior teeth. Patterns of over-eruption in different tooth types of marsupial carnivores are consistent with two non-exclusive mechanisms that operate in other mammals, a response to tooth wear and lack of an occlusal partner.
Biosynthetic Enzyme-guided Disease Correlation Connects Gut Microbial Metabolites Sulfonolipids to Inflammatory Bowel Disease Involving TLR4 Signaling
Authors: Older Ethan A. , Zhang Jian , Ferris Zachary E. , Xue Dan , Zhong Zheng , Mitchell Mary K. , Madden Michael , Wang Yuzhen , Chen Hexin , Nagarkatti Prakash , Nagarkatti Mitzi , Fan Daping , Ellermann Melissa , Li Yong-Xin , Li Jie
Published: March 2023

The trillions of microorganisms inhabiting the human gut are intricately linked to human health. At the species abundance level, correlational studies have connected specific bacterial taxa to various diseases. While the abundances of these bacteria in the gut serve as good indicators for disease progression, understanding the functional metabolites they produce is critical to decipher how these microbes influence human health. Here, we report a unique biosynthetic enzyme-guided disease correlation approach to uncover microbial functional metabolites as potential molecular mechanisms in human health. We directly connect the expression of gut microbial sulfonolipid (SoL) biosynthetic enzymes to inflammatory bowel disease (IBD) in patients, revealing a negative correlation. This correlation is then corroborated by targeted metabolomics, identifying that SoLs abundance is significantly decreased in IBD patient samples. We experimentally validate our analysis in a mouse model of IBD, showing that SoLs production is indeed decreased while inflammatory markers are increased in diseased mice. In support of this connection, we apply bioactive molecular networking to show that SoLs consistently contribute to the immunoregulatory activity of SoL-producing human microbes. We further reveal that sulfobacins A and B, two representative SoLs, primarily target Toll-like receptor 4 (TLR4) to mediate immunomodulatory activity through blocking TLR4’s natural ligand lipopolysaccharide (LPS) binding to myeloid differentiation factor 2, leading to significant suppression of LPS-induced inflammation and macrophage M1 polarization. Together, these results suggest that SoLs mediate a protective effect against IBD through TLR4 signaling and showcase a widely applicable biosynthetic enzyme-guided disease correlation approach to directly link the biosynthesis of gut microbial functional metabolites to human health.
Massively integrated coexpression analysis reveals transcriptional regulation, evolution and cellular implications of the noncanonical translatome
Authors: Rich April , Acar Omer , Carvunis Anne-Ruxandra
Published: March 2023

Background

Recent studies uncovered pervasive transcription and translation of thousands of noncanonical open reading frames (nORFs) outside of annotated genes. The contribution of nORFs to cellular phenotypes is difficult to infer using conventional approaches because nORFs tend to be short, of recentde novoorigins, and lowly expressed. Here we develop a dedicated coexpression analysis framework that accounts for low expression to investigate the transcriptional regulation, evolution, and potential cellular roles of nORFs inSaccharomyces cerevisiae.

Results

Our results reveal that nORFs tend to be preferentially coexpressed with genes involved in cellular transport or homeostasis but rarely with genes involved in RNA processing. Mechanistically, we discover that youngde novonORFs located downstream of conserved genes tend to leverage their neighbors’ promoters through transcription readthrough, resulting in high coexpression and high expression levels. Transcriptional piggybacking also influences the coexpression profiles of youngde novonORFs located upstream of genes, but to a lesser extent and without detectable impact on expression levels. Transcriptional piggybacking influences, but does not determine, the transcription profiles ofde novonORFs emerging nearby genes. About 40% of nORFs are not strongly coexpressed with any gene but are transcriptionally regulated nonetheless and tend to form entirely new transcription modules. We offer a web browser interface (https://carvunislab.csb.pitt.edu/shiny/coexpression/) to efficiently query, visualize and download our coexpression inferences.

Conclusions

Our results suggest that nORF transcription is highly regulated. Our coexpression dataset serves as an unprecedented resource for unraveling how nORFs integrate into cellular networks, contribute to cellular phenotypes, and evolve.
Neural Dynamic Underlying Coordination Process between Habitual and Goal-Directed Behavior
Authors: He Mengyang , Wen Wen , Qi Changzhu
Published: March 2023

The coordination between habitual and goal-directed behaviors has significant evolutionary importance. However, the specific cognitive processes and neural mechanisms underlying this coordination process require further research. Since inducing natural habitual responses through repetitive stimuli-response training in a laboratory environment is extremely difficult in humans, well-trained sports experts with automatic perception-action features towards expertise-related stimuli serve as ideal natural samples to address this critical gap. We conducted scalp EEG recordings while sports experts performed an expertise Simon task that involved both automatic and goal-directed processes with moderate space of expertise-related stimuli congruent or incongruent with the response hand. In the congruent condition, sports experts showed larger response-locked LRP and beta band (15-25Hz) activity at the frontal-central region, indicating an enhanced automatic response tendency towards expertise-related stimuli. In the incongruent condition, a larger theta (3-8Hz) dynamic was observed in the superior frontal gyrus when sports experts needed to inhibit the automatic response tendency. The results indicated that sports experts exhibited an enhanced coordination process towards expertise-related stimuli, which was closely related to specific cognitive processes of response preparation and response inhibition in coordinating habitual and goal-directed behaviors
Hierarchy and networks in the transcriptional response ofMycobacterium abscessusto antibiotics
Authors: Hurst-Hess Kelley , McManaman Charity , Yang Yong , Gupta Shamba , Ghosh Pallavi
Published: March 2023

Mycobacterium abscessuscauses acute and chronic pulmonary infection in patients with chronic lung damage. It is intrinsically resistance to antibiotics effective against other pathogenic mycobacteria largely due to the drug-induced expression of genes that confer resistance. Induction of genes upon exposure to ribosome targeting antibiotics proceeds via WhiB7-dependent and -independent pathways. WhiB7 controls the expression of >100 genes, a few of which are known determinants of drug resistance. The function of the vast majority of genes within the regulon is unknown, but some conceivably encode additional mechanisms of resistance. Furthermore, the hierarchy of gene expression within the regulon, if any, is poorly understood. In the present work we have identified 56 WhiB7 binding sites using chromatin immunoprecipitation sequencing (CHIP-Seq) which accounts for the WhiB7-dependent upregulation of 70 genes, and find thatM. abscessusWhiB7 functions exclusively as a transcriptional activator at promoters recognized by σA/σBWe have investigated the role of 18 WhiB7 regulated genes in drug resistance and demonstrated the role of MAB_1409c and MAB_4324c in aminoglycoside resistance. Further, we identify a σH-dependent pathway in aminoglycoside and tigecycline resistance which is induced upon drug exposure and is further activated by WhiB7 demonstrating the existence of a crosstalk between components of the WhiB7-dependent and -independent circuits.

Abstract Importance

The induction of multiple genes that confer resistance to structurally diverse ribosome-targeting antibiotics is funneled through the induction of a single transcriptional activator, WhiB7, by antibiotic-stalled ribosomes. This poses a severe restriction inM. abscessustherapy as treatment with one ribosome-targeting antibiotic confers resistance to all other ribosome-targeting antibiotics. Here we uncover the intricacies of the WhiB7 regulatory circuit, identify three previously unknown determinants of aminoglycoside resistance and unveil a communication between WhiB7 dependent and independent components. This not only expands our understanding of the antibiotic resistance potential ofM. abscessusbut can also inform the development of much needed therapeutic options.
Automated scoring of nematode nictation on a textured background
Authors: McClanahan Patrick D. , Golinelli Luca , Le Tuan Anh , Temmerman Liesbet
Published: March 2023

Entomopathogenic nematodes, includingSteinernemaspp., play an increasingly important role as biological alternatives to chemical pesticides. The infective juveniles of these worms use nictation – a behavior in which animals stand on their tails – as a host-seeking strategy. The developmentally-equivalent dauer larvae of the free-living nematodeCaenorhabditis elegansalso nictate, but as a means of phoresy or “hitching a ride” to a new food source. Advanced genetic and experimental tools have been developed forC. elegans, but time-consuming manual scoring of nictation slows efforts to understand this behavior, and the textured substrates required for nictation can frustrate traditional machine vision segmentation algorithms. Here we present a Mask R-CNN-based tracker capable of segmentingC. elegansdauers andS. carpocapsaeinfective juveniles on a textured background suitable for nictation, and a machine learning pipeline that scores nictation behavior. We use our system to show that the nictation propensity ofC. elegansfrom high-density liquid cultures largely mirrors their development into dauers, and to quantify nictation inS. carpocapsaeinfective juveniles in the presence of a potential host. This system is an improvement upon existing intensity-based tracking algorithms and human scoring which can facilitate large-scale studies of nictation and potentially other nematode behaviors.
Xiphoid nucleus of the midline thalamus controls cold-induced food seeking
Authors: Lal Neeraj K. , Le Phuong , Aggarwal Samarth , Zhang Alan , Wang Kristina , Qi Tianbo , Pang Zhengyuan , Yang Dong , Nudell Victoria , Yeo Gene W. , Banks Alexander S. , Ye Li
Published: March 2023

Maintaining body temperature is calorically expensive for endothermic animals. Mammals eat more in the cold to compensate for energy expenditure, but the neural mechanism underlying this coupling is not well understood. Through behavioral and metabolic analyses, we found that mice dynamically switch between energy conservation and food-seeking states in the cold, the latter of which is primarily driven by energy expenditure rather than the sensation of cold. To identify the neural mechanisms underlying cold-induced food seeking, we use whole-brain cFos mapping and found that the xiphoid (Xi), a small nucleus in the midline thalamus, was selectively activated by prolonged cold associated with elevated energy expenditure but not with acute cold exposure.In vivocalcium imaging showed that Xi activity correlates with food-seeking episodes in cold conditions. Using activity-dependent viral strategies, we found that optogenetic and chemogenetic stimulation of cold-activated Xi neurons recapitulated cold-induced feeding, whereas their inhibition suppressed it. Mechanistically, Xi encodes a context-dependent valence switch promoting food-seeking behaviors in cold but not warm conditions. Furthermore, these behaviors are mediated by a Xi to nucleus accumbens projection. Our results establish Xi as a key region for controlling cold-induced feeding, an important mechanism for maintaining energy homeostasis in endothermic animals.
Associations of cannabis use, tobacco use and incident anxiety, mood, and psychotic disorders: a systematic review and meta-analysis
Authors: Burke Chloe , Freeman Tom P , Sallis Hannah , Wootton Robyn E. , Burnley Annabel , Lange Jonas , Lees Rachel , Sawyer Katherine , Taylor Gemma
Published: March 2023

Importance

Traditional observational epidemiological studies have consistently found an association between tobacco use, cannabis use and subsequent mental ill-health. However, the extent to which this association reflects an increased risk of new-onset mental ill-health is unclear and may be biased by unmeasured confounding.

Objective

To examine the association between cannabis use, tobacco use and risk of incident mood, anxiety, and psychotic disorders, and explore risk of bias.

Data Sources

CINAHL, Embase, MEDLINE, PsycINFO and ProQuest Dissertation and Theses were searched from inception until November 2022, in addition to supplementary searches.

Study Selection

Longitudinal studies assessing tobacco use and cannabis use and their association with incident mood, anxiety or psychotic disorders were included. Studies conducted in populations selected on health status (e.g., pregnancy) or other highly-selected characteristics (e.g., incarcerated persons) were excluded.

Data Extraction and Synthesis

A modified Newcastle Ottawa Scale was used to assess study quality. The confounder matrix and E-Values were used to assess potential bias due to unmeasured confounding. Summary risk ratios (RR) were calculated in random-effects meta-analyses using the generic inverse variance method.

Main Outcome(s) and Measure(s)

Exposures were measured via self-report and defined through status (e.g., current use) or heaviness of use (e.g., cigarettes per day). Outcomes were measured through symptom-based scales, interviews, registry codes and self-reported diagnosis or treatment. Effect estimates extracted were risk of incident disorders by exposure status.

Results

Seventy-five out of 27789 records were included. Random effects meta-analysis demonstrated a positive association between tobacco use and mood disorder (RR:1.39, 95%CI:1.30–1.47) and psychotic disorder (RR:3.45, 95%CI:2.63-4.53), but not anxiety disorder (RR:1.21, 95%CI:0.87–1.68). Cannabis use was positively associated with psychotic disorders (RR:3.19, 95%CI:2.07-4.90), but not mood disorders (RR:1.31, 95%CI:0.92-1.86) or anxiety disorders (RR:1.10, 95%CI:0.99-1.22). Confounder matrix and E-value assessment indicated estimates were moderately biased by unmeasured confounding.

Conclusions and Relevance

This systematic review and meta-analysis presents evidence for a longitudinal, positive association between both substances and incident psychotic disorders and tobacco use and mood disorders. There was no evidence to support an association between cannabis use and common mental health conditions. Existing evidence across all outcomes was limited by inadequate adjustment for potential confounders. Future research should prioritise methods allowing for stronger causal inference, such as Mendelian randomization and evidence triangulation.
An Evidence Based Methodological Framework for Pandemic Preparedness to Support the Clinical Trial Unit Workforce
Authors: Phiri Peter , Shi Jian qing , Cavalini Heitor , Yardley Lucy , Barnard-Kelly Katherine , Sajid Sana , Raymont Vanessa , Rathod Shanaya , Delanerolle Gayathri
Published: March 2023

Aims: This study reports a new workforce preparedness framework for use during pandemics, specifically within clinical trials units. Methods: An evidence-based framework was developed using qualitative and quantitative data, as reported by the EPIC observational study. A framework methodology was used to analyse qualitative and quantitative data to identify themes. The themes were used to identify sub-themes that were codes with illustrative quotes. A logic model was develop using spatial features. Results: The qualitative component of the study included the views of 6 semi-structured interviews where discussions indicated the need for flexible working, requirement for better operational management, and access to electronic data systems remotely. Conclusion: Significant mental health impact on the CTU workforce can be prevented by the introduction of a framework to streamline operational delivery of research, providing flexible working patterns to the workforce, and improved access to health and wellbeing practices. Funding calls should be made available to conduct further workforce-based research in the UK and to develop evidence-based policies to better prepare for future pandemics.
Comparison of 2D and 3D oxygen-enhanced MRI of the placenta
Authors: Hubbard Cristinacce Penny L. , Patel Minal , Oh Alexander , Naish Josephine H. , Johnstone Edward D. , Ingram Emma
Published: March 2023

Oxygen-Enhanced Magnetic Resonance Imaging (OE-MRI) of the human placenta is potentially a sensitive marker of in vivo oxygenation. This methodological study shows that full coverage of the placenta is possible using 3D mapping of the change in longitudinal relaxation rate (ΔR1), in a group of healthy pregnant subjects breathing elevated levels of oxygen.

Twelve pregnant subjects underwent a comparison of 2D and 3D OE-MRI. ΔR1was mapped for a single 2D slice (ss-2D), a single matched-slice from the 3D volume (ss-3D) and the full 3D volume (vol-3D).

The group-average median ΔR1values for ss-3D (0.023 s-1) and vol-3D (0.022 s-1) do not differ significantly from ss-2D (0.020 s-1), when compared using a two-tailed paired t-test (ss-3D (p = 0.58) and vol-3D (p = 0.70)). However, median baseline T1(T1b) for ss-2D was higher (1603 ms) than T1bfor ss-3D (1540 ms, p=0.07) and significantly higher than vol-3D (1515 ms, p = 0.02), when compared using a two-tailed paired t-test. In contrast with previous studies, no correlation of median ΔR1with gestation age at scan for the normal group (N = 10) was observed for ss-2D, likely due to the smaller gestational range.

Full volume OE-MRI maps reveal sensitivity to changes in ΔR1, with some participants showing an enhanced gradient in the intermediate space between the fetal and maternal sides of the placenta in the 3D data. This study shows that it is feasible to acquire whole placental volume OE-MRI data on a Philips 1.5 T MRI scanner. Further work is necessary to implement this increased coverage on the scanners of other vendors.
First-in-human prospective trial of sonobiopsy in glioblastoma patients using neuronavigation-guided focused ultrasound
Authors: Yuan Jinyun , Xu Lu , Chien Chih-Yen , Yang Yaoheng , Yue Yimei , Fadera Siaka , Stark Andrew H. , Schwetye Katherine E. , Nazeri Arash , Desai Rupen , Athiraman Umeshkumar , Chaudhuri Aadel A. , Chen Hong , Leuthardt Eric C.
Published: March 2023

Sonobiopsy is an emerging technology that combines focused ultrasound (FUS) with microbubbles to enrich circulating brain disease-specific biomarkers for noninvasive molecular diagnosis of brain diseases. Here, we report the first-in-human prospective trial of sonobiopsy in glioblastoma patients to evaluate its feasibility and safety in enriching circulating tumor biomarkers. A nimble FUS device integrated with a clinical neuronavigation system was used to perform sonobiopsy following an established clinical workflow for neuronavigation. Analysis of blood samples collected before and after FUS sonication showed enhanced plasma circulating tumor biomarker levels. Histological analysis of surgically resected tumors confirmed the safety of the procedure. Transcriptome analysis of sonicated and unsonicated tumor tissues found that FUS sonication modulated cell physical structure-related genes but evoked minimal inflammatory response. These feasibility and safety data support the continued investigation of sonobiopsy for noninvasive molecular diagnosis of brain diseases.
Model-based optimization of controlled release formulation of levodopa for Parkinson’s disease
Authors: Arav Yehuda , Zohar Assaf
Published: March 2023

Levodopa is the current standard of care for Parkinson’s disease, but chronic therapy has been associated with motor complications. Maintaining sustained and constant blood concentrations may reduce these complications, but designing a controlled release formulation (CRF) that delivers such a profile is challenging. To facilitate the development of such formulation, we developed and validated a physiologically based mathematical model. Analysis of experimental results using the model shows that levodopa is well absorbed along the entire small intestine and that levodopa in the stomach causes fluctuations during the first 3 hours after administration. Based on these insights, we used the model to develop guidelines for an optimal CRF for different stages of PD. Such formulation is expected to produce steady concentrations and prolong therapeutic duration by 50% over a common CRF with a lower dose, thereby increasing the patient’s compliance with the dosage regime.
Quantitative LC-MS study of compounds found predictive of COVID-19 severity and outcome
Authors: Roberts Ivayla , Muelas Marina Wright , Taylor Joseph M. , Davison Andrew S. , Winder Catherine L. , Goodacre Royston , Kell Douglas B.
Published: March 2023

INTRODUCTION

Since the beginning of the SARS-CoV-2 pandemic in December 2019 multiple metabolomics studies have proposed predictive biomarkers of infection severity and outcome. Whilst some trends have emerged, the findings remain intangible and uninformative when it comes to new patients.

OBJECTIVES

In this study, we accurately quantitate a subset of compounds in patient serum that were found predictive of severity and outcome.

METHODS

A targeted LC-MS method was used in 46 control and 95 acute COVID-19 patient samples to quantitate the selected metabolites. These compounds included tryptophan and its degradation products kynurenine and kynurenic acid (reflective of immune response), butyrylcarnitine and its isomer (reflective of energy metabolism) and finally 3’,4’-didehydro-3’-deoxycytidine, a deoxycytidine analogue, (reflective of host viral defence response). We subsequently examine changes in those markers by disease severity and outcome relative to those of control patients’ levels.

RESULTS & CONCLUSION

Finally, we demonstrate the added value of the kynurenic acid / tryptophan ratio for severity and outcome prediction and highlight the viral detection potential of ddhC.
How have mathematical models contributed to understanding the transmission and control of SARS-CoV-2 in healthcare settings? A systematic search and review
Authors: Smith David R M , Chervet Sophie , Pinettes Théo , Shirreff George , Jijón Sofía , Oodally Ajmal , Jean Kévin , Opatowski Lulla , Kernéis Solen , Temime Laura
Published: March 2023

Background

Since the onset of the COVID-19 pandemic, mathematical models have been widely used to inform public health recommendations regarding COVID-19 control in healthcare settings.

Objectives

To systematically review SARS-CoV-2 transmission models in healthcare settings, and summarise their contributions to understanding nosocomial COVID-19.

Methods

Systematic search and review.

Data sources

Published articles indexed in PubMed.

Study eligibility criteria

Modelling studies describing dynamic inter-individual transmission of SARS-CoV-2 in healthcare settings, published by mid-February 2022.

Participants and interventions

Any population and intervention described by included models.

Assessment of risk of bias

Not appropriate for modelling studies.

Methods of data synthesis

Structured narrative review.

Results

Models have mostly focused on acute care and long-term care facilities in high-income countries. Models have quantified outbreak risk across different types of individuals and facilities, showing great variation across settings and pandemic periods. Regarding surveillance, routine testing – rather than symptom-based testing – was highlighted as essential for COVID-19 prevention due to high rates of silent transmission. Surveillance impacts were found to depend critically on testing frequency, diagnostic sensitivity, and turn-around time. Healthcare re-organization was also found to have large epidemiological impacts: beyond obvious benefits of isolating cases and limiting inter-individual contact, more complex strategies such as staggered staff scheduling and immune-based cohorting reduced infection risk. Finally, vaccination impact, while highly effective for limiting COVID-19 burden, varied substantially depending on assumed mechanistic impacts on infection acquisition, symptom onset and transmission. Studies were inconsistent regarding which individuals to prioritize for interventions, probably due to the high diversity of settings and populations investigated.

Conclusions

Modelling results form an extensive evidence base that may inform control strategies for future waves of SARS-CoV-2 and other viral respiratory pathogens. We propose new avenues for future models of healthcare-associated outbreaks, with the aim of enhancing their efficiency and contributions to decision-making.
Molecular Neuropathology and Cerebrospinal Fluid Diagnostic Biomarkers of SARS-Cov2 Infection in Central Nervous System– A Scoping Review Protocol
Authors: Kyaruzi Victor Meza , Mduma Emmanuel , Nyalundja Arsene Daniel , Bandyopadhyay Soham , Kamabu Larrey Kasereka , Atron Bydaa , Nathan Mugenyi , Itodo Daniel Jeremiah Oluwatomi , Elamin Zobidah Yousif , Marwa Boniphace Barnabas , Msemo Rajab , Naeem Ahmed , jean de Dieu Tumusifu Manegabe , Kumar Tarun Suvari , Tazoah Ngepgou Beckline , Chiazo Ugwoke Franklin , David Samuel Oreoluwa , Nsavyimana Yves Jacket , Bureta Constansia Anselim , Rutabasibwa Nicephorus , Mchome Laurent Lemeri , Shimber Emnet Tesfaye , Tirsit Abenezer , Mfinanga Sayoki , Hassen Getaw Worku , Abdellaziz Osama , Mwakigonja Amos
Published: March 2023

Introduction

Despite the broad spectrum of neurological symptomatic manifestation in COVID19 patients, the brain tissue susceptibility and permissiveness to SARS-Cov2 infection is yet uncertain. This critical appraisal aims at bridging the gap by consolidating the body of evidence for meticulous evaluation of molecular neuropathological pathways and CSF diagnostic signatures of SARS-Cov2 infection in the central nervous system (CNS) that will underpin further strategic approach for neuroprotection and treatment of neurological COVID19

Methods and Analysis

We have developed the protocol of this review according to the provisions of Joanna Briggs Institute Reviewer’s Manual for Evidence Synthesis, 2015 and Arksey and O Malley’s Methodological Framewotk, 2005. The articles for this review will be sourced from several electronic databases including EMBASE, PubMed, Scopus, Web of Science (WOS), Cochrane, Crossref Metadata and Semantic scholar. Herein we generated the search strategy using the medical subject headings [ MeSH Terms], term in all field bibliography at all permutations in conjunctions with boolean operators

Ethical Clearance and Dissemination plan

Herein the review will not involve the human participants henceforth the ethical clearance approval is not applicable. We will disseminate the final findings of this review to scientific conferences at local and international level. The manuscript for final findings will be published on reputable journal of neuroscience.
Estimating the importation risk of mpox virus in 2022 to Hong Kong, China
Authors: Xu Mingda , Shan Songwei , Shao Zengyang , Bai Yuan , Du Zhanwei , Wang Zhen , Gao Chao
Published: March 2023

International air travel has been recognized as a crucial factor in the cross-regional transmission of monkeypox (now known as mpox) since this disease rapidly spread across the globe in May 2022. On September 6, 2022, Hong Kong SAR (HK) reported its first imported mpox case with travel history of the United States (US), Canada, and the Philippines. In this study, we estimated the importation risk to HK from 25 international departures from May 1 to September 6, 2022, based on the prevalence of pre-symptomatic mpox cases in the study regions, and time-varying flight mobility evaluated by aggregating multiple open-access air travel datasets (e.g., OpenSky, Aviation Edge). The result indicated that the US had the most significant importation risk of 0.63 (95% CI: 0.32, 0.95) during the study period, followed by the United Kingdom (UK) and Canada with a risk of 0.29 (95% CI: 0.10, 0.63) and 0.17 (95% CI: 0.08, 0.32), respectively. Our study demonstrated that the importation risk of mpox from the US and Canada was substantially higher than other regions, which was aligned with the travel history of the first reported case in HK. Our study provided a simplified computational method for estimating the importation risk of mpox virus based on air travel mobility and disease prevalence. Estimating the international importation risk of mpox is essential for appropriately designing and timely adjusting emergency public health strategies and inbound measures.
Trends in Pediatric Firearm-Related Encounters during the COVID-19 Pandemic by Age Group, Race/Ethnicity, and Schooling Mode in Tennessee
Authors: McKay Tara , Gastineau Kelsey , Wrenn Jesse O. , Han Jin H. , Storrow Alan B.
Published: March 2023

Purpose

Increases in pediatric firearm-related injuries during the COVID-19 pandemic may be due to changes in where children and adolescents spent their time. This paper examines changes in the frequency of pediatric firearm-related encounters as a function of schooling mode overall and by race/ethnicity and age group at a large trauma center through 2021.

Methods

We use data from a large pediatric and adult trauma center in Tennessee from January 2018 to December 2021 (N=211 encounters) and geographically linked schooling mode data. We use Poisson regressions to estimate smoothed monthly pediatric firearm-related encounters as a function of schooling mode overall and stratified by race and age.

Results

Compared to pre-pandemic, we find a 42% increase in pediatric encounters per month during March 2020 to August 2020, when schools were closed, and a 23% increase in encounters after schools returned to in-person instruction. Effects of schooling mode are heterogeneous by race. Encounters increased among non-Hispanic Black children and adolescents across all periods relative to pre-pandemic. Among non-Hispanic white children and adolescents, encounters increased during the closure period and decreased on return to in-person instruction. Effects of schooling mode are also heterogeneous by age. Relative to pre-pandemic, pediatric firearm-related encounters increased 205% for children aged 5 to 11 and 69% for adolescents aged 12 to 15 during the school closure period.

Conclusion

COVID-19-related changes to school instruction mode in 2020 and 2021 are associated with changes in the frequency and composition of pediatric firearm-related encounters at a major trauma center in Tennessee.