bluuebunny/crossref_metadata_2025 huggingface dataset:
The current management of scaphoid fractures in the emergency department across an Australian metropolitan public health service: A retrospective cohort study
Authors: Chang Margaret Ting-Kwei , Price Maggie , Furness James , Kemp-Smith Kevin , Simas Vini , Pickering Rowan , Lenaghan Deborah
Published: September 2022

Background:

Scaphoid fractures are commonly present to emergency departments (EDs), challenging medical practitioners to achieve accurate diagnosis and management. This is because of the prevalence of radiographically occult scaphoid fractures and complications associated with missed diagnoses. Clinical Guidelines are limited for treatment of suspected scaphoid fractures, and heterogeneity in the literature further complicates management. This study aimed to explore the differences in management between practitioners in the ED and determine if immobilizing clinically suspected scaphoid fractures is supported by current evidence. This study also aimed to establish if there are predictors to assist in the diagnosis of a scaphoid fracture in the ED.

Methods:

A retrospective cohort study analyzed clinical data from patient’s charts who attended the ED for a scaphoid fracture in 2019. Using retrospective patient chart audits and a Data Extraction Form, the clinical data regarding the assessment, treatment, diagnosis, and follow-up outcomes were collected. Descriptive analysis and multivariable logistic regression were performed to assess current management and find out predictors of a scaphoid fracture.

Results:

There was significance between practitioners performing physical assessments and providing treatment (P < .001). Physiotherapists performed assessment and education combined treatment more frequently than nurse practitioners and doctors. Thirty-four cases (11.7%) were negative for fracture in ED and positive in follow-up at the orthopedic clinic. There was an estimated loss of income of $327,433.60 (Australian dollar) for 221 patients who missed work due to overtreatment with immobilization. The strongest predictors for a confirmed scaphoid fracture were of male gender (odds ratio, 3.2; 95% confidence interval, 2.1–5.0; P < .001) and a positive x-ray in ED (odds ratio, 36.6; 95% confidence interval, 17.4–77.0; P < .001).

Conclusion:

Management of scaphoid fractures across the Gold Coast Hospital Health Service ED followed commonly accepted practices involving x-ray and immobilization; however, this conservative approach to management is associated with increased health costs and low rates of conversion to a confirmed scaphoid fracture. Male gender was the only significant predictor associated with a scaphoid fracture.
A pilot retrospective study of comprehensive nursing care on psychological disorder in colorectal cancer undergoing chemotherapy
Authors: Zhang Zhou-Yi , Wang Rui , Zhang Li , Gu Ming-Li , Guan Xiu-E
Published: September 2022

Background:

This pilot study retrospectively evaluated the effects of comprehensive nursing care (CNC) on psychological disorders in patients with colorectal cancer (CC) undergoing chemotherapy.

Methods:

This study analyzed 70 eligible patients’ case records of CC undergoing chemotherapy. These records were allocated to a treatment group (n = 35) or a control group (n = 35). All 70 patients in both groups received routine nursing care. In addition, 35 patients in the treatment group also received CNC. The primary outcomes were anxiety, as measured by Self-rating Anxiety Scale, and depression, as assessed by Self-rating Depression Scale. The secondary outcomes were quality of life, as measured by The 36-Item Short Form Health Survey, and adverse events. All outcome data were analyzed before and 3-month after treatment.

Results:

At 3-month after treatment, the patients in the treatment group had better outcomes in the Self-rating Anxiety Scale (P<0.01), Self-rating Depression Scale (P<0.01), and The 36-Item Short Form Health Survey (social function, P = .04; emotional role, P = 0.03) than those in the control group. With regard to safety, no treatment-related adverse events were recorded in either group.

Conclusion:

The findings of this pilot retrospective study showed promising effects of CNC on psychological disorders and quality of life in patients with CC undergoing chemotherapy. However, more high-quality clinical trials are required to confirm these findings.
Mechanism of Astragali Radix for the treatment of osteoarthritis: A study based on network pharmacology and molecular docking
Authors: Shao Yiming , He Jiao , Zhang Xinan , Xie Panpan , Lian Hongkai , Zhang Meng
Published: September 2022

Osteoarthritis (OA) is a degenerative joint disease caused by many factors. Astragali Radix (Huangqi), a traditional Chinese medicine (TCM), is widely used to treat OA. Although it can inhibit the progression of OA, its pharmacological mechanism is unclear.

In this study, we used a network pharmacological approach to determine the mechanism by which Huangqi inhibits the progression of OA. We obtained the active ingredients of Huangqi from the Traditional Chinese Systems Pharmacology database and identified potential targets of these ingredients. Next, we identified the OA-related targets by using the GeneCards and Online Mendelian Inheritance in Man databases. Then, a protein–protein interaction (PPI) network was established based on the overlapping genes between the Huangqi targets and the OA targets, and the interactions were analyzed. Subsequently, the Metascape database was used to perform the Gene Ontology biological functions and Kyoto Encyclopedia of Genes and Genomes pathways enrichment analysis. Furthermore, selected active ingredients and corresponding targets were investigated through molecular docking.

In total, 20 active ingredients and 206 related targets were identified. The results of Gene Ontology enrichment analysis showed that the intersection targets were mainly involved in immune inflammation, proliferation, and apoptosis. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that Huangqi might exert antiosteoarthritis effect mainly through the PI3K–Akt signaling pathway, apoptosis, the mitogen-activated protein kinases signaling pathway, and the p53 signaling pathway. Moreover, the molecular docking results indicated that quercetin and kaempferol exhibited the good binding capacity to transcription factor JUN, tumor necrosis factor, and protein kinase B.

In summary, we investigated the therapeutic effects of Huangqi from a systemic perspective. These key targets and pathways provide promising directions for future studies to reveal the exact regulating mechanism of Huangqi against OA.
Neuronal signalling of zinc: from detection and modulation to function
Authors: Zhang Chen , Dischler Anna , Glover Kaitlyn , Qin Yan
Published: September 2022

Zinc is an essential trace element that stabilizes protein structures and allosterically modulates a plethora of enzymes, ion channels and neurotransmitter receptors. Labile zinc (Zn2+) acts as an intracellular and intercellular signalling molecule in response to various stimuli, which is especially important in the central nervous system. Zincergic neurons, characterized by Zn2+deposits in synaptic vesicles and presynaptic Zn2+release, are found in the cortex, hippocampus, amygdala, olfactory bulb and spinal cord. To provide an overview of synaptic Zn2+and intracellular Zn2+signalling in neurons, the present paper summarizes the fluorescent sensors used to detect Zn2+signals, the cellular mechanisms regulating the generation and buffering of Zn2+signals, as well as the current perspectives on their pleiotropic effects on phosphorylation signalling, synapse formation, synaptic plasticity, as well as sensory and cognitive function.
More than a ligand: PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I interferon pathway
Authors: Hodgins Jonathan J. , Abou-Hamad John , Hagerman Ash , Yakubovich Edward , Tanese de Souza Christiano , Marotel Marie , Buchler Ariel , Fadel Saleh , Park Maria M. , Fong-McMaster Claire , Crupi Mathieu F. , Bell John C. , Harper Mary-Ellen , Rotstein Benjamin H. , Auer Rebecca C. , Vanderhyden Barbara C. , Sabourin Luc A. , Bourgeois-Daigneault Marie-Claude , Cook David P. , Ardolino Michele
Published: September 2022

Targeting the PD-1/PD-L1 axis has transformed the field of immune-oncology. While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced infection with oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 suppressed type I interferon by promoting a metabolic shift characterized by enhanced glucose uptake and glycolysis rate. Lactate generated from glycolysis was the key metabolite responsible for inhibiting type I interferon responses and enhancing oncolytic virus infection in PD-L1-expressing cells. In addition to adding mechanistic insight into PD-L1 intrinsic function and showing that PD-L1 has a broader impact on immunity and cancer biology besides acting as a ligand for PD-1, our results will also help guide the numerous efforts currently ongoing to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.

Once sentence summary

PD-L1 promotes oncolytic virus efficacy.
Model discovery to link neural activity to behavioral tasks
Authors: Costabile Jamie D , Balakrishnan Kaarthik A , Schwinn Sina , Haesemeyer Martin
Published: September 2022

Brains are not engineered solutions to a well-defined problem but arose through selective pressure acting on random variation. It is therefore unclear how well a model chosen by an experimenter can relate neural activity to experimental conditions. Here we developed “Model identification of neural encoding (MINE).” MINE is an accessible framework using convolutional neural networks (CNN) to discover and characterize a model that relates aspects of tasks to neural activity . Although flexible, CNNs are difficult to interpret. We use Taylor decomposition approaches to understand the discovered model and how it maps task features to activity. We apply MINE to a published cortical dataset as well as experiments designed to probe thermoregulatory circuits in zebrafish. MINE allowed us to characterize neurons according to their receptive field and computational complexity, features which anatomically segregate in the brain. We also identified a new class of neurons that integrate thermosensory and behavioral information which eluded us previously when using traditional clustering and regression-based approaches.
Compartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage
Authors: Ghasemi David R. , Okonechnikov Konstantin , Rademacher Anne , Tirier Stephan , Maass Kendra K. , Schumacher Hanna , Sundheimer Julia , Statz Britta , Rifaioglu Ahmet S. , Bauer Katharina , Schumacher Sabrina , Bortolomeazzi Michele , Giangaspero Felice , Ernst Kati J. , Saez-Rodriguez Julio , Jones David T. W. , Kawauchi Daisuke , Mallm Jan-Philipp , Rippe Karsten , Korshunov Andrey , Pfister Stefan M. , Pajtler Kristian W.
Published: September 2022

Medulloblastoma with extensive nodularity (MBEN) are cerebellar tumors with two histologically distinct compartments and varying disease course. In some children MBEN progresses, while others show spontaneous differentiation into more benign tumors. However, the mechanisms that control the tug-of-war between proliferation and differentiation are not well understood. Here, we dissected this process with a multi-modal single cell transcriptome analysis. We found that the internodular MBEN compartment comprised proliferating early cerebellar granular neuronal precursors (CGNP)-like tumor cells as well as stromal, vascular, and immune cells. In contrast, the nodular compartment consisted of postmitotic, neuronally differentiated MBEN cells. Both compartments were connected through an intermediate cell stage of actively migrating CGNPs. Furthermore, astrocyte-like tumor cells were identified that had branched off the main CGNP developmental trajectory. Cells with an astroglial phenotype were found in close proximity to migrating, late CGNP-like and postmitotic neuronally differentiated cells. Our study reveals how the spatial tissue organization is linked to the developmental trajectory of proliferating tumor cells through a migrating precursor stage into differentiated tumor cells with a more benign phenotype. We anticipate that our framework for integrating single nucleus RNA-sequencing and spatial transcriptomics will help to uncover intercompartmental interactions also in other cancers with varying histology.
In silico evaluation of the role of the long non-coding RNA LINC00092 in thyroid cancer progression ; regulation of the miR-34a-5p/RCAN1 axis
Authors: Morovat Saman , Morovat Pejman , Kamali Mohammad Javad , Teimourian Shahram
Published: September 2022

Background

As the most prevalent endocrine cancer, thyroid cancer (TC) accounts for 1.7% of all cancer cases. A significant increase in TC morbidity has been observed over the past three decades. TC diagnosis has been reported to be problematic based on the current approach. As a result, it is imperative to develop molecular biomarkers to improve the accuracy of the diagnosis. An analysis of bioinformatics data was conducted in this study to analyze lncRNAs and their roles as ceRNAs associated with the development and progression of TC.

Materials and Method

The first step in this study was to collect RNA-seq data from the GDC database. Then, DESeq2 was used to analyze differentially expressed lncRNAs (DElncRNAs), miRNAs (DEMIs), and mRNAs (DEGs) between TC patients and healthy subjects. Our study identified DElnc-related miRNAs and miRNA-related genes to develop a lncRNA/miRNA/mRNA axis using online tools and screening. A co-expression analysis was performed to investigate correlations between DElncs and their associated mRNAs. Next, a protein-protein interaction (PPI) network was constructed. Functional enrichment and pathway enrichment were conducted on genes in the PPI network to discover additional biological activities among these molecules. Lastly, a correlation between the expression levels and the infiltration abundance of immune cells was assessed through immune infiltration analysis.

Results

There were 58 DElncs, 34 DEMIs, and 864 DEGs in thyroid tumor tissue and non-tumor tissue samples. Following validation of our lncRNA results with the intersection of differentially expressed lncRNAs in TCGA and GEPIA2, we selected two downregulated DElncs, including AC007743.1 and LINC00092, as the final research elements. We then performed an interaction analysis to predict lncRNAs-miRNAs and miRNAs-mRNAs interactions, which led to identifying the LINC00092/miR-34a-5p and miR-34a-5p/RCAN1 axis, respectively. There was a correlation between LINC00092 and RCAN1 according to Pearson correlation analysis. To improve our understanding of RCAN1, we developed a PPI network. According to the Immune Infiltration Analysis, RCAN1 expression was positively correlated with CD8+ T cells, macrophages, and neutrophils.

Conclusion

The results of this study suggest that LINC00092/miR-34a-5p/RCAN1 axis may have a functional role in the progression of TC. LINC00092 may be used as a promising biomarker for TC prognosis and may be a better diagnostic and therapeutic target.
Characterization of magnetic nanoparticles from the shells of freshwater mussel L fortunei and marine P perna mussels
Authors: Valadão Cardoso Antonio , Carvalho e Souza Clara , Dantas Maria Sylvia , Machado Camila Schults , Fraga Freitas Erico Tadeu , Krohling Alisson Carlos , do Rosário Veronica A Martins , Dias Heinene Luiz G
Published: September 2022

The presence of magnetic nanoparticles in animal species, including humans, has been growing steadily, but none have reported the presence in mollusks apart from the radula of chitons, in 1962. In shells this is the first time. Magnetite (Fe3O4) nanoparticles were extracted (using three distinct and rather simple protocols) from the shells of freshwater Limnoperna fortunei (Dunker 1857) and marine Perna perna (Linnaeus 1758) mussels and were fully physically-chemically characterized. Due to the spatial distribution, the ferrimagnetic particles in the shells are in low concentration and present a superparamagnetic behavior characteristic of materials of nanometric sizes. Transmission electron microscopy (TEM, especially HRTEM) indicated that the 50-100 nm round magnetic particles are in fact aggregates of 5-10 nm nanoparticles. Using analysis TEM techniques on the shell of the L fortunei we have not found any iron oxide particle at the periostracum layer nor in the calcite layer. Nevertheless, roughly round nanoparticle aggregates of iron hydroxy/oxide were found in the nacar layer, the aragonite layer. Being the aragonite layer responsible for more than 97% of the shell of the L fortunei and considering the estimated size of magnetic nanoparticles we could infer that they might be distributed throughout the nacar layer.
Metaplasticity: Dark exposure boosts excitability and visual plasticity in adult human cortex
Authors: Min Seung Hyun , Wang Zili , Chen Mengting , Hu Rongjie , Gong Ling , He Zhifen , Wang Xiaoxiao , Hess Robert F. , Zhou Jiawei
Published: September 2022

Abstract

An interlude of dark exposure for about one week is known to shift the excitatory/inhibitory (E/I) balance of the mammalian visual cortex, promoting cortical plasticity across species and accelerating visual recovery in animals that have experienced cortical lesions during development. However, the translational impact of our understanding of dark exposure from animal studies on humans remains elusive. Here, we use magnetic resonance spectroscopy as a probe for E/I balance in the primary visual cortex (V1) to determine the effect of 60-min dark exposure, and measure binocular combination as a behavioral assay to assess visual plasticity in 18 normally sighted human adults (13 females). To induce neuroplastic changes in the observers, 60-min monocular deprivation was performed, which is known to shift sensory eye balance in favor of the previously deprived eye. We report that prior dark exposure strengthens cortical excitability in V1 and boosts visually plasticity in normal adults. Our findings are surprising, given the fact that the interlude is very brief. We present direct evidence that an environmental manipulation that reduces intracortical inhibition can act as a metaplastic facilitator for visual plasticity in adult humans.
Deletion or inhibition of PTPRO mitigates diet-induced hepatic steatosis and inflammation in obesity
Authors: Shintani Takafumi , Suzuki Ryoko , Takeuchi Yasushi , Shirasawa Takuji , Noda Masaharu
Published: September 2022

Chronic inflammation plays crucial roles in obesity-induced metabolic diseases. We herein demonstrated that mice lacking the protein tyrosine phosphatase receptor type O (PTPRO) exhibited the hyper-obese phenotype when fed a high-fat/high-sucrose diet. However, Ptpro-KO mice with hyperobesity showed the markedly small accumulation of ectopic fat in the liver, improvements in lipid and glucose homeostasis, and low-grade systemic inflammation associated with low macrophage activation. Expression of protein tyrosine phosphatase 1b (Ptp1b), an enzyme which is known to be implicated in metabolic disorders, was also suppressed in Ptpro-KO mice. The administration of AKB9778, a specific inhibitor of PTPRO, to highly obese ob/ob mice reproduced the phenotypes of Ptpro-KO mice along with the amelioration of inflammation. We revealed that an increase in the phosphorylation of Tyr(117) in vimentin, a component of intermediate filaments, by the inhibition of PTPRO promoted the growth of lipid droplets in adipocytes. The improvement in metabolic conditions with the attenuation of inflammation in Ptpro-KO mice was explained by the low activation of NFκb, a key transcription factor for inflammatory response, in adipose tissue. This is the first study to show that PTPRO is a promising target to ameliorate hepatic steatosis and metabolic disorders.
High-Resolution Magnetization-Transfer Imaging of Post-Mortem Marmoset Brain: Comparisons with Relaxometry and Histology
Authors: Marschner Henrik , Pampel André , Müller Roland , Reimann Katja , Bock Nicolas , Morawski Markus , Geyer Stefan , Möller Harald E.
Published: September 2022

Cell membranes and macromolecules or paramagnetic compounds interact with water proton spins, which modulates magnetic resonance imaging (MRI) contrast providing information on tissue composition. For a further investigation, quantitative magnetization transfer (qMT) parameters (at 3T), including the ratio of the macromolecular and water proton pools, ℱ, and the exchange-rate constant as well as the (observed) longitudinal and the effective transverse relaxation rates (at 3T and 7T), and respectively, were measured at high spatial resolution (200 μm) in a slice of fixed marmoset brain and compared to histology results obtained with Gallyas’ myelin stain and Perls’ iron stain. and were linearly correlated with the iron content for the entire slice, whereas distinct differences were obtained between gray and white matter for correlations of relaxometry and qMT parameters with myelin content. The combined results suggest that the macromolecular pool interacting with water consists of myelin and (less efficient) non-myelin contributions. Despite strong correlation of ℱ and none of these parameters was uniquely specific to myelination. Due to additional sensitivity to iron stores, and were more sensitive for depicting microstructural differences between cortical layers than ℱ.

Highlights

MRI (200μm) is correlated with myelin and iron histology in fixed marmoset brain.

Detailed z-spectra are employed for precise magnetization-transfer (MT) measurements.

Longitudinal and effective transverse relaxation rates depend linearly on tissue iron.

Longitudinal relaxation and MT are not uniquely specific to myelin.

Myelin and non-myelin macromolecules impact water relaxation and MT contrast.
Exposure to global change and microplastics elicits an immune response in an endangered coral
Authors: Bove Colleen B. , Greene Katharine , Sugierski Sharla , Kriefall Nicola G. , Huzar Alexa K. , Hughes Annabel M. , Sharp Koty , Fogarty Nicole D. , Davies Sarah W.
Published: September 2022

Global change is increasing seawater temperatures and decreasing oceanic pH, driving declines of coral reefs globally. Coral ecosystems are also impacted by local stressors, including microplastics, which are ubiquitous on reefs. While the independent effects of these global and local stressors are well-documented, their interactions remain less explored. Here, we examine the independent and combined effects of global change (ocean warming and acidification) and microplastics exposures on gene expression (GE) and microbial community composition in the endangered coral Acropora cervicornis. Nine genotypes were fragmented and maintained in one of four experimental treatments: 1) ambient conditions (ambient seawater, no microplastics; AMB); 2) microplastics treatment (ambient seawater, microplastics; MP); 3) global change conditions (warm and acidic conditions, no microplastics; OAW); and 4) multistressor treatment (warm and acidic conditions with microplastics; OAW+MP) for 22 days, after which corals were sampled for genome-wide GE profiling and ITS and 16S metabarcoding. Overall A. cervicornis GE responses to all treatments were subtle; however, corals in the multistressor treatment exhibited the strongest GE responses, and genes associated with innate immunity were overrepresented in this treatment, according to gene ontology enrichment analyses. 16S analyses revealed stable microbiomes dominated by the bacterial associate Aquarickettsia, suggesting that these A. cervicornis fragments exhibited remarkably low variability in bacterial community composition. Future work should focus on functional differences across microbiomes, especially Aquarickettsia and viruses, in these responses. Overall, results suggest that local stressors present a unique challenge to endangered coral species under global change.
Graded optogenetic activation of the auditory pathway for hearing restoration
Authors: Mittring Artur , Moser Tobias , Huet Antoine
Published: September 2022

Optogenetic control of neural activity enables innovative approaches to improve functional restoration of diseased sensory and motor systems. For clinical translation to succeed, optogenetic stimulation needs to closely match the coding properties of the targeted neuronal population and employ suitable emitters at their optimal operation. This requires tailoring of channelrhodopsins, emitters and coding strategies. Here, we provide a framework to parametrize optogenetic neural control and apply it to the auditory pathway that requires high temporal fidelity of stimulation. We used viral gene transfer of the ultrafast targeting-optimized Chronos into spiral ganglion neurons (SGNs) of the cochlea. We characterized the light-evoked response byin vivorecordings from individual SGNs and neurons of the anteroventral cochlear nucleus (AVCN) that detect coincident SGN input. Our results demonstrate that spike probability of SGNs can be gradually dialed by adjusting the width of light pulses of constant intensity, which optimally serves efficient laser diode operation. We identified an effective pulse width of 1.6 ms to maximize information encoding in SGNs. An upper boundary of optical stimulation rates results from robust spike rate adaptation that required a few tens of milliseconds to recover. We developed a semi-stochastic stimulation paradigm to rapidly (within minutes) estimate the transfer function from light to SGNs firing. The semi-stochastic stimulus evoked firing of different statistics allowing to approximate the time constant of neuronal integration in the AVCN. Our data pave the way to design the sound coding strategies of future optical cochlear implants.
An Alpha-helical Lid Guides the Target DNA toward Catalysis in CRISPR-Cas12a
Authors: Saha Aakash , Ahsan Mohd , Arantes Pablo R. , Schmitz Michael , Chanez Christelle , Jinek Martin , Palermo Giulia
Published: September 2022

CRISPR-Cas12a is a powerful RNA-guided genome-editing system, also emerging as a robust diagnostic tool that cleaves double-stranded DNA using only the RuvC domain. This opens an overarching question on how the spatially distant DNA target strand (TS) traverses toward the RuvC catalytic core. Here, continuous tens of microsecond-long molecular dynamics and free-energy simulations reveal that an ⍺-helical lid, located within the RuvC domain, plays a pivotal role in the traversal of the TS by anchoring the crRNA:TS hybrid and elegantly guiding the TS toward the RuvC core, as also corroborated by DNA cleavage experiments. In this mechanism, the REC2 domain pushes the crRNA:TS hybrid toward the core of the enzyme, while the Nuc domain aids the bending and accommodation of the TS within the RuvC core by bending inward. Understanding of this cardinal process in the functioning of Cas12a will enrich fundamental knowledge and facilitate further engineering strategies for genome-editing.
Spreading depolarization causes reperfusion failure after cerebral ischemia
Authors: Törteli Anna , Tóth Réka , Berger Sarah D. , Samardzic Sarah , Bari Ferenc , Menyhárt Ákos , Farkas Eszter
Published: September 2022

Background

Despite successful recanalization to treat acute ischemic stroke, reperfusion failure associated with poor functional outcomes develops in half of the patients. The cause of reperfusion failure remains the subject of intensive research. Here, we explore the possibility that spreading depolarization (SD), a potent ischemic injury mechanism is a significant contributor and reliable predictor of reperfusion failure.

Methods

Young adult male and female C57BL/6 mice (n=69) were anesthetized with isoflurane (0.6-0.9%) and prepared for transcranial optical imaging. After 10 min of baseline, incomplete global forebrain ischemia was induced by transient (45 min) bilateral common carotid artery (CCA) occlusion, followed by 75 min reperfusion. SD and cerebral blood flow (CBF) changes were visualized with intrinsic optical signal imaging and laser speckle contrast imaging. To block SD, the irreversible NMDA receptor antagonist MK801 was applied (0.3 mg/kg, i.p., n=29). Neurological deficit was evaluated at baseline and post-ischemia with a composite Garcia Neuroscore scale. Collaterals of the circle of Willis were examined after loading the vasculature with carbon black ink. Ischemic neuronal injury was evaluated in hematoxylin-eosin-stained brain sections.

Results

SD emerged after ischemia onset in one or both hemispheres under a perfusion threshold (CBF drop to 21.1±4.6 vs. 33.6±4.4 %, SD vs. no SD). The failure of later reperfusion (44.4±12.5 %) was invariably linked to previous ischemic SD. In contrast, reperfusion was adequate (98.9±7.4 %) in hemispheres devoid of SD during ischemia. CBF reduced below the perfusion threshold of SD, when the P1 segment was absent in the circle of Willis. SD occurrence and the linked reperfusion failure were associated with poor neurologic function, and greater neuronal necrosis. The inhibition of SD with MK801 significantly improved reperfusion.

Conclusions

SD occurrence during ischemia impairs later reperfusion, prognosticating poor functional outcomes. The increased likelihood of SD occurrence is predicted by inadequate collaterals.
A machine learning liver-on-a-chip system for safer drug formulation
Authors: Shi Yunhua , Lin Chih-Hsin , Reker Daniel , Steiger Christoph , Hess Kaitlyn , Collins Joy E. , Tamang Siddartha , Ishida Keiko , Lopes Aaron , Wainer Jacob , Hayward Alison M. , Walesky Chad , Goessling Wolfram , Traverso Giovanni
Published: September 2022

Drug metabolism leads to biotransformations of pharmaceutical substances that alter drug efficacy, toxicity, as well as drug interactions. Modeling these processes ex vivo stands to greatly accelerate our capacity to develop safe and efficacious drugs and formulations. Recognizing the liver as the primary site of drug metabolism, here we report a novel whole-tissue ex vivo liver screening platform that enabled modeling of hepatic metabolism and tracking of hepatotoxic drug metabolites. We applied the system for the characterization of acetaminophen (APAP) metabolism and identified interactions that can mitigate the generation of toxic metabolites ex vivo. Combining our experimental platform with state-of-the-art machine learning, we validated two novel functional excipients that can prevent APAP hepatotoxicity in vivo in mice. To assess translational potential, we prototyped a novel solid dosage form with controlled release of both APAP and our functional excipients. Our this platform provides innovative potential access to actionable data on drug metabolism to support the development of new therapeutic approaches.
White matter structural bases for predictive tapping synchronization
Authors: García-Saldivar Pamela , de León Cynthia , Concha Luis , Merchant Hugo
Published: September 2022

We determined the intersubject association between rhythmic entrainment abilities of human subjects during a synchronization continuation tapping task (SCT) and the macro and microstructural properties of their superficial (SWM) and deep (dWM) white matter. Diffusion-weighted images were obtained from 32 subjects who also performed the SCT with auditory or visual metronomes and five tempos ranging from 550 to 950 ms. We developed a method to determine the fiber density of U-fibers running tangentially to the cortex. Notably, the right audiomotor system showed individual differences in the density of U-fibers that were correlated with the degree of predictive entrainment across subjects. These correlations were selective for the synchronization epoch with auditory metronomes and were specific for tempos around 1.5 Hz. In addition, there was a significant association between predictive rhythmic entrainment and the density and bundle diameter of the corpus callosum (CC), forming a chronotopic map where behavioural correlations of short and long intervals were found with the anterior and posterior portions of the CC. Finally, the fiber bundle cross-section of the arcuate fasciculus, the CC, and the Superior Longitudinal Fasciculus showed a significant correlation with the mean asynchronies of the auditory SCT. These findings suggest that the structural properties of the SWM and dWM in the audiomotor system support the predictive abilities of subjects during rhythmic tapping, where the density of cortical U-fibers are linked to the preferred tapping tempo, and the bundle properties of CC define an interval selective topography that has an anterior posterior gradient.
Heart Is Deceitful Above All Things: threat expectancy induces the illusory perception of increased heartrate
Authors: Parrotta Eleonora , Bach Patric , Perrucci Mauro Gianni , Costantini Marcello , Ferri Francesca
Published: September 2022

The perception of the internal milieu is thought to reflect beliefs and prior knowledge about the expected state of the body, rather than only actual interoceptive states. This study investigated whether heartbeat perception could be illusorily distorted towards prior subjective beliefs, such that threat expectations suffice to induce a false perception of increased heartbeat frequency. Participants were instructed to focus on their cardiac activity and report their heartbeat, either tapping along to it (Experiment 1) or silently counting (Experiment 2) while ECG was recorded. While completing this task, different cues provided valid predictive information about the intensity of an upcoming cutaneous stimulation (high- vs. low- pain). Results showed that participants expected a heart rate increase over the anticipation of high- vs. low-pain stimuli and that this belief was perceptually instantiated, as shown by their interoceptive reports. Importantly, the perceived increase was not mirrored by the real heart rate. Perceptual modulations were absent when participants executed the same task but with an exteroceptive stimulus (Experiment 3). The findings reveal, for the first time, an interoceptive illusion of increased heartbeats elicited by threat expectancy and shed new light on interoceptive processes through the lenses of Bayesian predictive processes, providing tantalizing insights into how such illusory phenomena may intersect with the recognition and regulation of people’s internal states.
Visual object topographic motifs emerge from self-organization of a unified representational space
Authors: Doshi Fenil R. , Konkle Talia
Published: September 2022

The object-responsive cortex of the visual system has a highly systematic topography, with a macro-scale organization related to animacy and the real-world size of objects, and embedded meso-scale regions with strong selectivity for a handful of object categories. Here, we use self-organizing principles to learn a topographic representation of the data manifold of a deep neural network representational space. We find that a smooth mapping of this representational space showed many brain-like motifs, with (i) large-scale organization of animate vs. inanimate and big vs. small response preferences, supported by (ii) feature tuning related to textural and coarse form information, with (iii) naturally emerging face- and scene-selective regions embedded in this larger-scale organization. While some theories of the object-selective cortex posit that these differently tuned regions of the brain reflect a collection of distinctly specified functional modules, the present work provides computational support for an alternate hypothesis that the tuning and topography of the object-selective cortex reflects a smooth mapping of a unified representational space.
Reorganizing Niche Architecture Still Preserves Organ Function in the Hair Follicle
Authors: Wei Haoyang , Du Shuangshuang , Parksong Jeeun , Pasolli H. Amalia , Regot Sergi , Gonzalez Lauren E. , Xin Tianchi , Greco Valentina
Published: September 2022

Stem cells’ ability to build and replenish tissues depends on support from their niche. While niche architecture varies across different organs, the functional importance of niche architecture is unclear. During hair follicle growth, multipotent epithelial progenitors build hair via crosstalk with their remodeling fibroblast niche, the dermal papilla, providing a powerful model to functionally interrogate different niche architectures. Through intravital imaging, we show that dermal papilla fibroblasts remodel both individually and collectively to form a polarized, structurally robust niche. Polarized TGFβ signaling precedes structural niche polarity, and loss of TGFβ signaling in dermal papilla fibroblasts leads them to progressively lose their stereotypic architecture and instead surround the epithelium. The reorganized niche relocates multipotent progenitors, but nevertheless supports their proliferation and differentiation. However, progenitor differentiation is completed prematurely, resulting in compromised hair production. Overall, our results reveal that niche architecture optimizes organ efficiency, but is not absolutely essential for organ function.
Bicistronic expression of a high-performance calcium indicator and opsin yields stable, robust cortical expression for holographic two-photon stimulation
Authors: LaFosse Paul K. , Zhou Zhishang , Friedman Nina G. , Deng Yanting , Akitake Bradley , Histed Mark H.
Published: September 2022

Patterns of activity across many neurons are fundamental units of neural computation. Two-photon holographic photostimulation allows both delivering input to, and imaging responses from, patterns or populations of neurons. However, to make this method an easily-deployable tool, simple methods are needed to robustly and stably express opsins and indicators in the same cells. Here we describe a bicistronic adeno-associated virus (AAV) that in transfected cells expresses both the fast and bright calcium indicator GCaMP8s, and a soma-targeted (st) and two-photon-activatable opsin, ChrimsonR. With this method, in the visual cortex of mice, stChrimsonR stimulation with two-photon holography drives robust spiking in targeted cells, and neural responses to visual sensory stimuli and spontaneous activity are strong and easy to measure. stChrimsonR is a good choice of opsin when a balance is needed between stimulation-laser activatability and avoidance of imaging laser activation. This approach is a simple and robust way to prepare neurons in vivo for two-photon holography and imaging.

Significance statement

The recent advent of holographic photostimulation methods in conjunction with standard two-photon calcium imaging promises unprecedented levels of control in manipulating and dissecting brain circuitry in vivo while reading out neural activity. These all-optical methods rely on a working synergy between optogenetic strategies to both measure calcium activity through genetically-encoded calcium indicators and modulate cell activity through light-activated opsins. Genetic strategies to achieve reliable and stable co-expression of opsin and indicator remain sparse and often challenging to execute. Here, we present a genetic tool to achieve robust co-expression of jGCaMP8s indicator and stChrimsonR opsin via a single injected virus to help facilitate experiments aiming to use holography to investigate the circuit principles underlying brain activity.
High-Frequency Stimulation Does Not Improve Comfort of Transcutaneous Spinal Cord Stimulation
Authors: Dalrymple Ashley N , Hooper Charli Ann , Kuriakose Minna G , Capogrosso Marco , Weber Douglas J
Published: September 2022

Spinal cord neuromodulation has gained much attention for demonstrating improved motor recovery in people with spinal cord injury, motivating the development of clinically applicable technologies. Among them, transcutaneous spinal cord stimulation (tSCS) is attractive because of its non-invasive profile. Many tSCS studies employ a high-frequency (10 kHz) carrier, which has been reported to reduce stimulation discomfort. However, these claims have come under scrutiny in recent years. The purpose of this study was to determine whether high-frequency tSCS is more comfortable at therapeutic amplitudes, which evoke posterior root-muscle (PRM) reflexes. In 16 neurologically intact participants, tSCS was delivered using a 1-ms long monophasic pulse with and without a high-frequency carrier. Stimulation amplitude and pulse duration were varied and PRM reflexes were recorded from the soleus, gastrocnemius, and tibialis anterior muscles. Participants rated their discomfort during stimulation from 0-10 at PRM reflex threshold. At PRM reflex threshold, high-frequency stimulation (0.87 ± 0.2) was equally comfortable as conventional stimulation (1.03 ± 0.18) but required approximately double the charge to evoke the PRM reflex (conventional: 32.4 ± 9.2 µC; high-frequency: 62.5 ± 11.1 µC). Strength-duration curves for high-frequency stimulation had a rheobase that was 4.8X greater and a chronaxie that was 5.7X narrower than the conventional monophasic pulse, indicating that high-frequency stimulation was less efficient in recruiting neural activity in spinal roots. High-frequency tSCS is equally as comfortable as conventional stimulation at amplitudes required to stimulate spinal dorsal roots.

GRAPHICAL ABSTRACT
Wildfires change plant scents but not pollinator attraction in a Mediterranean palm
Authors: García Yedra , Clara Castellanos María , Pausas Juli G.
Published: September 2022

Natural fire regimes are currently changing worldwide. These alterations may affect not only plant and animal species but also their interactions. Recently, a few studies have shown the effects of different disturbances on pollination through changes on plant fragrances mediating this interaction, yet no studies have focused on the effects of fires. Here, we assessed whether wildfires can modify plant scents and, in turn, pollinator attraction in a widespread palm in the western Mediterranean Basin. We studied the fireadapted palm Chamaerops humilis and its nursery (dominant in unburnt sites) and nonnursery (dominant in recently burnt sites) beetle pollinators. In nursery pollination systems, where pollinators develop inside their host plant, volatile organic compounds (VOCs) emitted by plants to attract pollinators can be crucial because of the tight interdependence among the interacting species. However, these systems can also involve non-nursery copollinators whose importance is context dependent, and potentially relevant for plant success after disturbance. We first compare scent composition between plants growing in burned and unburned sites after recent wildfires; then we conducted olfactory bioassays with the two beetle pollinators. Fires changed the palm’s scent composition; however, the two pollinators responded similarly to scent from burnt and unburnt areas which may ensure plant reproduction even after recent fire events. We show, for the first time, that wildfires can alter plant fragrances mediating mutualistic interactions, and that flexible pollinator responses to variable odourscapes can enhance resilience in plant performance.
Decoding Attended Spatial Location during Complex Scene Analysis with fNIRS
Authors: Ning Matthew , Yücel Meryem A. , Von Lühmann Alexander , Boas David A. , Sen Kamal
Published: September 2022

When analyzing complex scenes, humans often focus their attention on an object at a particular spatial location. The ability to decode the attended spatial location would facilitate brain computer interfaces for complex scene analysis. Here, we investigated functional near-infrared spectroscopy’s (fNIRS) capability to decode audio-visual spatial attention in the presence of competing stimuli from multiple locations. We targeted dorsal frontoparietal network including frontal eye field (FEF) and intra-parietal sulcus (IPS) as well as superior temporal gyrus/planum temporal (STG/PT). They all were shown in previous functional magnetic resonance imaging (fMRI) studies to be activated by auditory, visual, or audio-visual spatial tasks. We found that fNIRS provides robust decoding of attended spatial locations for most participants and correlates with behavioral performance. Moreover, we found that FEF makes a large contribution to decoding performance. Surprisingly, the performance was significantly above chance level 1s after cue onset, which is well before the peak of the fNIRS response. Our results demonstrate that fNIRS is a promising platform for a compact, wearable technology that could be applied to decode attended spatial location and reveal contributions of specific brain regions during complex scene analysis.
Avoiding misleading estimates using mtDNA heteroplasmy statistics to study bottleneck size and selection
Authors: Giannakis Konstantinos , Broz Amanda K. , Sloan Daniel B. , Johnston Iain G.
Published: September 2022

Mitochondrial DNA (mtDNA) heteroplasmy samples can shed light on vital developmental and genetic processes shaping mtDNA populations. The sample mean and sample variance of a set of heteroplasmy observations are typically used both to estimate bottleneck sizes and to perform fits to the theoretical “Kimura” distribution in seeking evidence for mtDNA selection. However, each of these applications raises problems. Sample statistics do not generally provide optimal fits to the Kimura distribution and so can give misleading results in hypothesis testing, including false positive signals of selection. Using sample variance can give misleading results for bottleneck size estimates, particularly for small samples. These issues can and do lead to false positive results for mtDNA mechanisms – all published experimental datasets we re-analysed, reported as displaying departures from the Kimura model, do not in fact give evidence for such departures. Here we outline a maximum likelihood approach that is simple to implement computationally and addresses all of these issues. We advocate the use of maximum likelihood fits and explicit hypothesis tests, not fits and Kolmogorov-Smirnov tests via summary statistics, for ongoing work with mtDNA heteroplasmy.
Vitamin B12 produced by gut bacteria modulates excitatory neurotransmission
Authors: Kang Woo Kyu , Araya Antonia , Fox Bennett W. , Thackeray Andrea , Schroeder Frank C. , Walhout Albertha J.M. , Alkema Mark J.
Published: September 2022

A growing body of evidence indicates that gut microbiota influence brain function and behavior. However, the molecular basis of how gut bacteria modulate host nervous system function is largely unknown. Here we show that vitamin B12-producing bacteria that colonize the intestine can modulate excitatory synaptic transmission and behavior in the host Caenorhabditis elegans. We find that vitamin B12 reduces cholinergic signaling in the nervous system through rewiring of the methionine (Met)/S-Adenosylmethionine (SAM) cycle in the intestine. We identify a conserved metabolic crosstalk between the Met/SAM cycle and the choline oxidation pathway. We show that metabolic rewiring of these pathways by vitamin B12 reduces cholinergic transmission by limiting the availability of free choline required by neurons to synthesize acetylcholine. Our study reveals a gut-brain communication pathway by which enteric bacteria modulate host behavior and may affect mental health.