bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Poor Sleep on Cardiovascular Disease-Free Life Expectancy: A Multi-Resource-Based Population Cohort Study
Authors: Huang Bo-Huei , del Pozo Cruz Borja , Teixeira-Pinto Armando , Cistulli Peter A. , Stamatakis Emmanuel
Published: October 2022

Background

The complexity of sleep hinders the formulation of sleep guidelines. Recent studies suggest that different unhealthy sleep characteristics jointly increase the risks for cardiovascular disease (CVD). This study aimed to estimate the differences in CVD-free life expectancy between people with different sleep profiles.

Methods

We included 308683 middle-aged adults from the UK Biobank among whom 140181 had primary care data linkage. We used an established composite sleep score comprising self-reported chronotype, duration, insomnia complaints, snoring, and daytime sleepiness to derive three sleep categories: poor, intermediate, and healthy. We also identified three clinical sleep disorders captured by primary care and inpatient records within two years before enrollment in the cohort: insomnia, sleep-related breathing disorders, and other sleep disorders. We estimated sex-specific CVD-free life expectancy with three-state Markov models conditioning on survival at age 40 across different sleep profiles and clinical disorders.

Results

We observed a gradual loss in CVD-free life expectancy toward poor sleep such as, compared with healthy sleepers, poor sleepers lost 1·80 [95% CI 0·96-2·75] and 2·31 [1·46-3·29] CVD-free years in females and males, respectively, while intermediate sleepers lost 0·48 [0·41-0·55] and 0·55 [0·49-0·61] years. Among men, those with clinical insomnia or sleep-related breathing disorders lost CVD-free life by 3·84 [0·61-8·59] or 6·73 [5·31-8·48] years, respectively. Among women, sleep-related breathing disorders or other sleep disorders were associated with 7·32 [5·33-10·34] or 1·43 [0·20-3·29] years lost, respectively.

Conclusions

Both self-reported and doctor-diagnosed poor sleep are negatively associated with CVD-free life, especially pronounced in participants with sleep-related breathing disorders.
Activity-regulated growth of motoneurons at the neuromuscular junction is mediated by NADPH oxidases
Authors: Sobrido-Cameán Daniel , Oswald Matthew C. W. , Bailey David M. D. , Mukherjee Amrita , Landgraf Matthias
Published: October 2022

Neurons respond to changes in the levels of activity they experience in a variety of ways, including structural changes at pre- and postsynaptic terminals. An essential plasticity signal required for such activity-regulated structural adjustments are reactive oxygen species (ROS). To identify sources of activity-regulated ROS required for structural plasticityin vivowe used theDrosophilalarval neuromuscular junction as a highly tractable experimental model system. For adjustments of presynaptic motor terminals, we found a requirement for both NADPH oxidases, Nox and Dual Oxidase (Duox), that are encoded in theDrosophilagenome. This contrasts with the postsynaptic dendrites from which Nox is excluded. NADPH oxidases generate ROS to the extracellular space. Here, we show that two aquaporins, Bib and Drip, are necessary ROS conduits in the presynaptic motoneuron for activity regulated, NADPH oxidase dependent changes in presynaptic motoneuron terminal growth. Our data further suggest that different aspects of neuronal activity-regulated structural changes might be regulated by different ROS sources: changes in bouton number require both NADPH oxidases, while activity-regulated changes in the number of active zones might be modulated by other sources of ROS. Overall, our results show NADPH oxidases as important enzymes for mediating activity-regulated plasticity adjustments in neurons.
Real-time Emotion Detection by Quantitative Facial Motion Analysis
Authors: Saadon Jordan R. , Yang Fan , Burgert Ryan , Mohammad Selma , Gammel Theresa , Sepe Michael , Rafailovich Miriam , Mikell Charles B. , Polak Pawel , Mofakham Sima
Published: October 2022

Background

Research into mood and emotion has often depended on slow and subjective self-report, highlighting a need for rapid, accurate, and objective assessment tools.

Methods

To address this gap, we developed a method using digital image speckle correlation (DISC), which tracks subtle changes in facial expressions invisible to the naked eye, to assess emotions in real-time. We presented ten participants with visual stimuli triggering neutral, happy, and sad emotions and quantified their associated facial responses via detailed DISC analysis.

Results

We identified key alterations in facial expression (facial maps) that reliably signal changes in mood state across all individuals based on these data. Furthermore, principal component analysis of these facial maps identified regions associated with happy and sad emotions. Compared with commercial deep learning solutions that use individual images to detect facial expressions and classify emotions, such as Amazon Rekognition, our DISC-based classifiers utilize frame-to-frame changes. Our data show that DISC-based classifiers deliver substantially better predictions, and they are inherently free of racial or gender bias.

Limitations

Our sample size was limited, and participants were aware their faces were recorded on video. Despite this, our results remained consistent across individuals.

Conclusions

We demonstrate that DISC-based facial analysis can be used to reliably identify an individual’s emotion and may provide a robust and economic modality for real-time, noninvasive clinical monitoring in the future.

Highlights

We detected the emotional state of participants in the absence of visible changes in facial expressions

We identified distinct facial movement maps for happy and sad emotions

We developed a highly sensitive, noninvasive, noncontact emotional state assessment tool
Corticospinal Responses Following Gait-Specific Training in Stroke Survivors: A Systematic Review
Authors: Cherni Yosra , Tremblay Alexia , Simon Margaux , Bretheau Floriane , K. Blanchette Andréanne , Mercier Catherine
Published: October 2022

Background

Corticospinal excitability is subject to alterations after stroke. While the reversal of these alterations has been proposed as an underlying mechanism for improvement walking capacity after gait-specific training, this has not yet been clearly demonstrated. Therefore, the objective of this review is to evaluate the effect of gait-specific training on corticospinal excitability in stroke survivors.

Design

Systematic review of the literature

Methods

We conducted an electronic database search in four databases (i.e., Medline, Embase, CINAHL and Web of Science) in June 2022. Two authors independently screened and selected all studies that investigated the effect of gait-specific training in post-stroke individuals on variables such as motor-evoked potential amplitude, motor threshold, map size, latency, and corticospinal silent period.

Results

Nineteen studies investigating the effect of gait-specific training on corticospinal excitability were included. Some studies showed an increased MEP amplitude (7/16 studies), a decreased latency (5/7studies), a decreased motor threshold (4/8 studies), an increased map size (2/3 studies) and a decreased cortical silent period (1/2 study) after gait-specific training. No change has been reported in term of short interval intracortical inhibition after training. Five studies did not report any significant effect after gait-specific training on corticospinal excitability.

Conclusion

The results of this systematic review suggest that gait-specific training modalities can drive neuroplastic adaptation among stroke survivors. However, given the methodological disparity of the included studies, further clinical trials with better methodological quality are needed to draw conclusions. Hence, the findings from this review can serve as a rationale for future studies and continued efforts in investigating the effects of gait-specific training on the central nervous system.
Machine learning models for predicting severe COVID-19 outcomes in hospitals
Authors: Wendland Philipp , Schmitt Vanessa , Zimmermann Jörg , Häger Lukas , Göpel Siri , Schenkel-Häger Christof , Kschischo Maik
Published: October 2022

The aim of this observational retrospective study is to improve early risk stratification of hospitalized Covid-19 patients by predicting in-hospital mortality, transfer to intensive care unit (ICU) and mechanical ventilation from electronic health record data of the first 24 hours after admission. Our machine learning model predicts in-hospital mortality (AUC=0.918), transfer to ICU (AUC=0.821) and the need for mechanical ventilation (AUC=0.654) from a few laboratory data of the first 24 hours after admission. Models based on dichotomous features indicating whether a laboratory value exceeds or falls below a threshold perform nearly as good as models based on numerical features. We devise completely data-driven and interpretable machine-learning models for the prediction of in-hospital mortality, transfer to ICU and mechanical ventilation for hospitalized Covid-19 patients within 24 hours after admission. Numerical values of CRP and blood sugar and dichotomous indicators for increased partial thromboplastin time (PTT) and glutamic oxaloacetic transaminase (GOT) are amongst the best predictors.
Identifying trends in SARS-CoV-2 RNA in wastewater to infer changing COVID-19 incidence: Effect of sampling frequency
Authors: Chan Elana M. G. , Kennedy Lauren C. , Wolfe Marlene K. , Boehm Alexandria B.
Published: October 2022

SARS-CoV-2 RNA concentrations in wastewater solids and liquids are correlated with reported incident COVID-19 cases. Reporting of incident COVID-19 cases has changed dramatically with the availability of at-home antigen tests. Wastewater monitoring therefore represents an objective tool for continued monitoring of COVID-19 occurrence. One important use case for wastewater data is identifying when there are sustained changes or trends in SARS-CoV-2 RNA concentrations. Such information can be used to inform public health messaging, testing, and vaccine resources. However, there is limited research on best approaches for identifying trends in wastewater monitoring data. To fill this knowledge gap, we applied three trend analysis methods (relative strength index (RSI), percent change (PC), Mann-Kendall (MK) trend test) to daily measurements of SARS-CoV-2 RNA in wastewater solids from a wastewater treatment plant to characterize trends. Because daily measurements are not common for wastewater monitoring programs, we also conducted a downsampling analysis to determine the minimum sampling frequency necessary to capture the trends identified using the “gold standard” daily data. The PC and MK trend test appear to perform similarly and better than the RSI in terms of early warning signaling for increasing and decreasing trends, so we only considered the PC and MK trend test methods in the downsampling analysis. Using an acceptable sensitivity and specificity cutoff of 0.5, we found that a minimum of 4 samples/week and 5 samples/week is necessary to detect trends identified by daily sampling using the PC and MK trend test method, respectively. If a higher sensitivity and specificity is needed, then more samples per week would be needed. Public health officials can adopt these trend analysis approaches and sampling frequency recommendations to wastewater monitoring programs aimed at providing information on how incident COVID-19 cases are changing in the contributing communities.
Poorer Sleep Health is Associated With Altered Brain Activation During Cognitive Control Processing in Healthy Adults
Authors: Smevik Hanne , Habli Sarah , Saksvik Simen Berg , Kliem Elisabeth , Evensmoen Hallvard Røe , Conde Virginia , Petroni Agustin , Asarnow Robert F. , Dennis Emily L. , Eikenes Live , Kallestad Håvard , Sand Trond , Thompson Paul M. , Saksvik-Lehouillier Ingvild , Håberg Asta Kristine , Olsen Alexander
Published: October 2022

This study investigated how proactive and reactive cognitive control processing in the brain was associated with habitual sleep health. BOLD fMRI data was acquired from 81 healthy adults with normal sleep (41 females, age 20.96 - 39.58 years) during a test of cognitive control (Not-X CPT). Sleep health was assessed in the week before MRI scanning, using both objective (actigraphy) and self-report measures. Multiple measures indicating poorer sleep health - including later/more variable sleep timing, later chronotype preference, more insomnia symptoms and lower sleep efficiency - were associated with stronger and more widespread BOLD activations in fronto-parietal and subcortical brain regions during cognitive control processing (adjusted for age, sex, education, and fMRI task performance). Most associations were found forreactivecognitive control activation, indicating that poorer sleep health is linked to a ‘hyper-reactive’ brain state. Analysis of time-on-task effects showed that, with longer time on task, poorer sleep health was predominantly associated with increasedproactivecognitive control activation, indicating recruitment of additional neural resources over time. Finally, shorter objective sleep duration was associated with lower BOLD activation with time on task and poorer task performance. In conclusion, even in ‘normal sleepers’, relatively poorer sleep health is associated with altered cognitive control processing, possibly reflecting compensatory mechanisms and / or inefficient neural processing.
Functional Integration of 3D-Printed Cerebral Cortical Tissue into a Brain Lesion
Authors: Jin Yongcheng , Mikhailova Ellina , Lei Ming , Cowley Sally , Sun Tianyi , Yang Xingyun , Zhang Yujia , Liu Kaili , Catarino Daniel , Soares Luana Campos , Bandiera Sara , Szele Francis G. , Molnar Zoltan , Zhou Linna , Bayley Hagan
Published: October 2022

Engineering human tissue with diverse cell types and desired cellular architectures and functions is a considerable challenge. The cerebral cortex, which has a layered cellular architecture composed of layer-specific neurons organised into vertical columns, delivers higher cognition through intricately wired neural circuits. However, current tissue engineering approaches cannot produce such structures. Here, we use a droplet printing technique to fabricate tissues comprising simplified cerebral cortical columns. Human induced pluripotent stem cells (hiPSCs) were differentiated into upper- and deep-layer neural progenitors, which were then printed to form cerebral cortical tissues with a two-layer organization. The tissues showed layer-specific biomarker expression and developed an integrated network of processes. Implantation of the printed cortical tissues into mouse brain explants resulted in substantial implant-host integration across the tissue boundaries as demonstrated by the projection of processes, the migration of neurons and the appearance of correlated Ca2+signals. The approach we have developed might be used for the evaluation of drugs and nutrients that promote tissue integration. Importantly, our approach might be applied in personalised implantation treatments that restore the cellular structure and function of a damaged brain by using 3D tissues derived from a patient’s own iPSCs.
Protein kinase A gene knockout inCoprinopsis cinereaby CRISPR/Cas9 RNP complex system
Authors: Chan Po Lam , Kwan Hoi Shan , Chang JinHui
Published: October 2022

Coprinopsis cinereais a model mushroom for studying the developmental processes of homobasidiomycetous fungi. The development ofC. cinereadepends on the sensing of environmental conditions, such as light, temperature, humidity and nutrients. The signal transduction pathway from the environmental condition sensors to the regulators and reproduction is an important research topic as the knowledge on it is still fragmentary. Protein kinases not only are crucial to the signal transduction, but also can be master switches of development. However, information on their role in basidiomycetous fungi is still limited. Using the effective gene-targeting of the current gene modification, a system of CRISPR/ Cas9 RNP with double strain template donor that contained a selective mark hygromycin cassette was developed in this study. In this system,CcPka1gene knockout was successfully generated through homologues repair together with Cas9 RNP complexes. This was the first report to use CRISPR/ Cas9 RNP approach with C. cinerea. ΔCcPka1mutants showed slow mycelial growth and rapid fruiting body induction compared to the wild type even when under high glucose condition. In addition, ΔCcPka1mutants had significantly increased intracellular glucose level and decreased glycogen level. Moreover, ΔCcPka1mutants regulated the gene expression of components in cAMP-PKA pathway. All these results demonstrated that PKA played an important role in the nutrient signal transduction and negatively regulated the fruiting body formation. This study also confirmed that GSK3 could be the downstream target of PKA, but their interaction requires further investigation.
Nonhuman primates exploit the prior assumption that the visual world is vertical
Authors: Khazali Mohammad Farhan , Daddaoua Nabil , Thier Peter
Published: October 2022

When human subjects tilt their heads in dark surroundings, the noisiness of vestibular information impedes precise reports on objects’ orientation with respect to earth’s vertical axis. This difficulty is mitigated if a vertical visual background is available. Tilted visual backgrounds induce feelings of head tilt in subjects who are in fact upright. This is often explained as a result of the brain resorting to the prior assumption that natural visual backgrounds are vertical. Here, we tested whether monkeys show comparable perceptual mechanisms. To this end we trained two monkeys to align a visual arrow to a vertical reference line that had variable luminance across trials, while including a large, clearly visible background square whose orientation changed from trial to trial. On around 20% of all trials, the vertical reference line was left out to measure the subjective visual vertical (SVV). When the frame was upright, the monkeys’SVVwas aligned with the gravitational vertical. In accordance with the perceptual reports of humans, however, when the frame was tilted, it induced an illusion of head tilt as indicated by a bias inSVVtowards the frame orientation. Thus all primates exploit the prior assumption that the visual world is vertical.
An alternative malonyl-CoA producing pathway in nature
Authors: Liu Bo , Zhang Yuwei , Cui Qianqian , Wu Sheng , Tang Shuangyan , Chen Yihua , Ma Yanhe , Liu Weifeng , Tao Yong
Published: October 2022

Malonyl-CoA is a key metabolic intermediate for biosynthesis of diverse cellular molecules and natural products. Carboxylation of acetyl-CoA is almost the unique pathway for malonly-CoA biosynthesis. Biotechnological production of numerous value-added malonyl-CoA-derived chemicals require high intracellular supply of malonyl-CoA. However, because of the central role of acetyl-CoA in primary metabolism, it is difficult to develop flexible strategies to balance malonyl-CoA supply with other cellular metabolism. Here we find that there is a natural alternative malonyl-CoA-producing pathway, in which the key reaction is catalyzed by an α-keto acid dehydrogenase complex BkdFGH fromStreptomyces avermitilis. This dehydrogenase complex could efficiently catalyze biosynthesis of malonyl-CoA from oxaloacetate in addition to recognizing its native substrate branched-chain α-keto acid. Oxaloacetate dehydrogenase (OADH) was shown to play important physiological roles during the regulation of biosynthesis of native malonyl-CoA-derived polyketides inStreptomyces. Furthermore, the oxlaocetate dehydrogenation reaction is thermodynamically superior to acetyl-CoA carboxylation and enable efficient bioproduction of diverse malonyl-CoA-derived chemicals in engineeringEscherichia coli. This novel malonyl-CoA source thus has great potential in the biotechnological field.
Neural mechanisms underlying uninstructed orofacial movements during reward-based learning behaviors
Authors: Li Wanru , Nakano Takashi , Mizutani Kohta , Matsubara Takanori , Kawatani Masahiro , Mukai Yasutaka , Danjo Teruko , Ito Hikaru , Aizawa Hidenori , Yamanaka Akihiro , Petersen Carl C. H. , Yoshimoto Junichiro , Yamashita Takayuki
Published: October 2022

During reward-based learning tasks, animals make orofacial movements that globally influence brain activity at the timings of reward expectation and acquisition. These orofacial movements are not explicitly instructed and typically appear along with goal-directed behaviors. Here we show that reinforcing optogenetic stimulation of midbrain dopamine neurons (oDAS) in mice is sufficient to induce orofacial movements in the whiskers and nose without accompanying goal-directed behaviors. Pavlovian conditioning with a sensory cue and oDAS elicited cue-locked and oDAS aligned orofacial movements, which were distinguishable by a machine learning model. Inhibition or knock-out of dopamine D1 receptors in the nucleus accumbens inhibited oDAS-induced motion but spared cue-locked motion, suggesting differential neural regulation of these two types of orofacial motions. In contrast, inactivation of the whisker primary motor cortex (wM1) abolished both types of orofacial movements. We found specific neuronal populations in wM1 representing either oDAS-aligned or cue-locked whisker movements. Notably, optogenetic stimulation of wM1 neurons successfully replicated these two types of movements. Our results thus suggest that accumbal D1 receptor-dependent and -independent neuronal signals converge in the wM1 for facilitating uninstructed orofacial movements during a reward-based learning task.
Structure of the Calvin-Benson-Bassham sedoheptulose-1,7-bisphosphatase from the model microalgaChlamydomonas reinhardtii
Authors: Le Moigne Théo , Santoni Martina , Jomat Lucile , Lemaire Stéphane D. , Zaffagnini Mirko , Chéron Nicolas , Henri Julien
Published: October 2022

The Calvin-Benson-Bassham cycle (CBBC) performs carbon fixation in photosynthetic organisms. Among the eleven enzymes that participate in the pathway, sedoheptulose-1,7-bisphosphatase (SBPase) is expressed in photo-autotrophs and catalyzes the hydrolysis of sedoheptulose-1,7- bisphosphate (SBP) to sedoheptulose-7-phosphate (S7P). SBPase, along with nine other enzymes in the CBBC, contributes to the regeneration of ribulose-1,5-bisphosphate, the carbon-fixing co- substrate used by ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). The metabolic role of SBPase is restricted to the CBBC, and a recent study revealed that the three-dimensional structure of SBPase from the mossPhyscomitrium patenswas found to be similar to that of fructose-1,6- bisphosphatase (FBPase), an enzyme involved in both CBBC and neoglucogenesis. In this study we report the first structure of an SBPase from a chlorophyte, the model unicellular green microalgaChlamydomonas reinhardtii. By combining experimental and computational structural analyses, we describe the topology, conformations and quaternary structure ofChlamydomonas reinhardtiiSBPase (CrSBPase). We identify active site residues and locate sites of redox- and phospho-post- translational modifications that contribute to enzymatic functions. Finally, we observe thatCrSBPase adopts distinct oligomeric states that may dynamically contribute to the control of its activity.
Phagosome-mediated activation of STING during diverse bacterial infections
Authors: Ragland Stephanie A. , Kagan Jonathan C.
Published: October 2022

Central to health and disease are innate immune receptors that bind bacterial molecules to initiate inflammation and host defense. Beyond pathogens and their membrane disruptive activities, mechanisms enabling bacterial molecules to access innate immune receptors in the cytoplasm are unknown. Here, we describe the cytoplasmic cyclic dinucleotide (CDN)-binding protein STING as a common bacterial sensor. Irrespective of virulence and after bacteriolysis in phagolysosomes, CDNs produced during infections with evolutionarily diverse bacteria activate STING. Of the several known CDN transporters, two supported bacteria-induced STING activation. We propose a connection between phagocytosis and STING that ensures host-bacteria interactions result in STING activation.
Excitable dynamics in a molecularly-explicit model of cell motility: Mixed-mode oscillations and beyond
Authors: Plazen Lucie , Khadra Anmar
Published: October 2022

Mesenchymal cell motility is mainly regulated by two members of the Rho-family of GTPases, called Rac and Rho. The mutual inhibition exerted by these two proteins on each other’s activation and the promotion of Rac activation by an adaptor protein called paxillin have been implicated in driving cellular polarization comprised of front (high active Rac) and back (high active Rho) during cell migration. Mathematical modeling of this regulatory network has previously shown that bistability is responsible for generating a spatiotemporal pattern underscoring cellular polarity called wave-pinning when diffusion is included. We previously developed a 6D reaction-diffusion model of this network to decipher the role of Rac, Rho and paxillin (along with other auxiliary proteins) in generating wave-pinning. In this study, we simplify this model through a series of steps into an excitable 3D ODE model comprised of one fast variable (the scaled concentration of active Rac), one slow variable (the maximum paxillin phosphorylation rate – turned into a variable) and a very slow variable (a recovery rate – also turned into a variable). We then explore, through slow-fast analysis, how excitability is manifested by showing that the model can exhibit relaxation oscillations (ROs) as well as mixed-mode oscillations (MMOs) whose underlying dynamics are consistent with a delayed Hopf bifurcation. By reintroducing diffusion and the scaled concentration of inactive Rac into the model, we obtain a 4D PDE model that generates several unique spatiotemporal patterns that are relevant to cell motility. These patterns are then characterized and their impact on cell motility are explored by employing the cellular potts model (CPM). Our results reveal that wave pinning produces purely very directed motion in CPM, while MMOs allow for meandering and non-motile behaviours to occur. This highlights the role of MMOs as a potential mechanism for mesenchymal cell motility.
Polygenic Effects on the Z Chromosome Underlie Hybrid Incompatibility inPapilioandHeliconiusButterflies
Authors: Xiong Tianzhu , Tarikere Shreeharsha , Rosser Neil , Li Xueyan , Yago Masaya , Mallet James
Published: October 2022

The fitness of animal hybrids follows two empirical rules: hybrids of the heterogametic sex aremore unfit (Haldane’s Rule), and the sex chromosome is disproportionately involved in incompatibility (the large-X/Z effect). Whether these rules result from genetic mechanisms shared across taxa remains unknown, and existing explanations rarely consider female heterogametic taxa such as butterflies. Here, we investigate hybrid incompatibilities inPapilioandHeliconiusbutterflies, and show that defects coincide with unbalanced introgression between the Z chromosome and its genetic background. This polygenic mechanism predicts both rules because introgressed ancestry on the Z chromosome is more skewed in females, and is more variable than on all autosomes. Therefore, the explanation for both rules in butterflies shares little similarity with prevailing theories relying on dominance.
Quorum sensing peptidic inhibitor rescue host immune system eradication: a novel QS infectivity mechanism
Authors: Yehuda Avishag , Malach Einav , Slamti Leyla , Kuo Shanny Shuan , Lau Jonathan Z. , Oh Myung Whan , Adeoye John , Shlezinger Neta , Lau Gee W. , Lereclus Didier , Hayouka Zvi
Published: October 2022

Subverting the host immune system is a major task for any given pathogen to assure its survival and proliferation. For the opportunistic human pathogenBacillus cereus(Bc), immune evasion enables the establishment of potent infections. In various species of the Bc group, the pleiotropic regulator PlcR and its cognate cell–cell signaling peptide PapR7regulates virulence genes expression in response to fluctuations in population density,i.e., a quorum-sensing (QS) system. However, how QS exerts its effects during infections, and whether PlcR confers the immune evading ability remain unclear. Herein, we report how interception of the QS communication in Bc obliterates the ability to control the host immune system. Here we designed a peptide-based QS inhibitor that suppresses PlcR-dependent virulence factor expression and attenuates Bc infectivity in mouse models. We demonstrate that the QS peptidic inhibitor blocks host immune system-mediated eradication by reducing the expression of PlcR-regulated major toxins. Our findings provide the first evidence that Bc infectivity is regulated by QS circuit mediated destruction of the host immunity, thus reveal a new strategy to limit Bc virulence and enhance host defense. This peptidic quorum-quenching agent constitutes readily accessible chemical tool for studying how other pathogen QS systems modulate host immunity and forms a basis for development of anti-infective therapeutics.
Unified control of temporal and spatial scales of sensorimotor behavior through neuromodulation of short-term synaptic plasticity
Authors: Zhou Shanglin , Buonomano Dean V.
Published: October 2022

Neuromodulators such as dopamine have been shown to modulate short-term synaptic plasticity (STP). Here we propose that the neuromodulation of STP provides a general mechanism to scale neural dynamics and motor outputs in time and space. We trained RNNs that incorporated STP to produce complex motor trajectories—handwritten digits—with different temporal (speed) and spatial (size) scales. The learned dynamics underwent temporal and spatial scaling when higher synaptic release probabilities corresponded to higher speed/size. Neuromodulation of STP enhanced temporal or spatial generalization compared to weight modulation alone. The model accounted for the data of two experimental studies involving flexible sensorimotor timing. Our results address a long-standing debate regarding the role of dopamine in timing and predict novel mechanisms by which dopamine may slow down neural dynamics and thus slow “clock” speed.
Adaptation to overflow metabolism by mutations that impair tRNA modification in experimentally evolved bacteria
Authors: Muraski Marc , Nilsson Emil M. , Fritz Melissa J , Richardson Anthony R. , Alexander Rebecca W. , Cooper Vaughn S.
Published: October 2022

When microbes grow in foreign nutritional environments, selection may enrich mutations in unexpected pathways connecting growth and homeostasis. An evolution experiment designed to identify beneficial mutations inBurkholderia cenocepaciacaptured six independent nonsynonymous substitutions in the essential genetilS, which modifies tRNAIle2by adding a lysine to the anticodon for faithful AUA recognition. Further, five additional mutants acquired mutations in tRNAIle2, which strongly suggests that disrupting the TilS:tRNAIle2interaction was subject to strong positive selection. Mutated TilS incurred greatly reduced enzymatic function but retained capacity for tRNAIle2binding. Yet both mutant sets outcompeted wild-type by decreasing lag phase duration by ∼3.5 hours. We hypothesized that lysine demand could underlie fitness in the experimental conditions. As predicted, supplemental lysine complemented the ancestral fitness deficit, but so did additions of several other amino acids. Mutant fitness advantages were also specific to rapid growth on galactose using oxidative overflow metabolism that generates redox imbalance, not resources favoring more balanced metabolism. Remarkably, 13tilSmutations also evolved in the Long-Term Evolution Experiment withE. coli, including four fixed mutations. These results suggest that TilS or unknown binding partners contribute to improved growth under conditions of rapid sugar oxidation at the predicted expense of translational accuracy.
Defining the roles of pyruvate oxidation, TCA cycle, and mannitol metabolism in methicillin resistanceStaphylococcus aureuscatheter-associated urinary tract infection
Authors: Paudel Santosh , Guedry Sarah , Obernuefemann Chloe LP , Hultgren Scott , Walker Jennifer N , Kulkarni Ritwij
Published: October 2022

Methicillin resistantStaphylococcus aureus(MRSA) is an important cause of complicated urinary tract infection (UTI) associated with the use of indwelling urinary catheters. Previous reports have revealed host and pathogen effectors critical for MRSA uropathogenesis. Here, we sought to determine the significance of specific metabolic pathways during MRSA UTI. First, we identified 16 mutants from the Nebraska transposon mutant library in the MRSA JE2 background with significantly reduced growth in pooled human urine (HU). Among these, five genes targeted by transposon mutation also showed significant upregulation upon exposure to HU for 2 h. This prompted us to generate transposon insertion mutants in the uropathogenic MRSA 1369 strain that were defective in TCA cycle (ΔsucD, ΔfumC), mannitol metabolism (ΔmtlD), and pyruvate oxidation and branched chain fatty acid synthesis (ΔlpdA). Compared to the WT, the ΔlpdAmutant showed a significant defect growth in HU and colonization of the urinary tract and dissemination to spleen in the mouse model of catheter-associated UTI (CAUTI), which may be attributed to its increased membrane hydrophobicity and higher susceptibility to killing in blood. MRSA 1369 ΔsucD, ΔfumC, and ΔmtlDmutants were not defective forin vitrogrowth in HU but showed significant fitness defects in the CAUTI mouse model. Overall, identification of novel metabolic pathways important for the urinary fitness and survival of MRSA can be used for the development of novel therapeutics.

Importance

WhileStaphylococcus aureushas historically not been considered a uropathogen,S. aureusurinary tract infection (UTI) is clinically significant in certain patient populations, including those with chronic indwelling urinary catheters. Moreover, mostS. aureusstrains causing catheter-associated UTI (CAUTI) are methicillin-resistantS. aureus(MRSA), which is difficult to treat as it limits treatment options and has the potential to deteriorate into life-threatening bacteremia, urosepsis, and shock. In this study, we found that pathways involved in pyruvate oxidation, TCA cycle, and mannitol metabolism are important for MRSA fitness and survival in the urinary tract. Improved understanding of the metabolic needs of MRSA in the urinary tract may help us develop novel inhibitors of MRSA metabolism that can be used to treat MRSA-CAUTI more effectively.
Incidence and Economic Burden of Retinal Tears in the United States
Authors: Taneja Kamil , Diaz Michael Joseph , Taneja Tanisha , Patel Karan , Batchu Sai , Oak Solomon , Zhang Alex , Joshi Aditya , Patel Urvish K.
Published: October 2022

Purpose

To characterize retinal tears (RTs) and calculate the economic burden of RTs that present to the emergency department (ED) in the US.

Methods

We used a large national ED database to retrospectively analyze RTs that presented to the ED from 2006 to 2019. Using extrapolation methods, national estimates of RT incidence, demographics, comorbidities, disposition, inpatient (IP) costs, and ED costs were calculated.

Results

During the time period between 2006 and 2019, 15,841 patients presented to the ED with RT as the primary diagnosis. RT incidence was stable at 8.2 per million US population (95% Confidence Interval (CI): 5.3 - 21.0) in this time period. Most patients were males, Caucasian, paid with private insurance, and admitted to EDs in the Northeast. The most common comorbidities were hypertension (19%), a history of cataracts (15%), and diabetes (7.2%).

During this time period, RTs costs added up to more than $79 million and $33 million in the ED and IP settings, respectively. Mean per-patient ED and IP costs increased by 145% (p=0.0008) and 86% (p=0.0047), respectively.

Conclusion

Despite the stable incidence of RTs, RTs place a significant economic burden to the healthcare system, which increases yearly. We recommend physicians and policy makers to work together to pass laws that could prevent the increasing healthcare costs.
Disentangling the role of NAc D1 and D2 cells in hedonic eating
Authors: Guillaumin Mathilde C. C. , Viskaitis Paulius , Bracey Ed , Burdakov Denis , Peleg-Raibstein Daria
Published: October 2022

Overeating is driven by both the hedonic component (‘liking’) of food, and the motivation (‘wanting’) to eat it. The nucleus accumbens (NAc) is a key brain center implicated in these processes, but how distinct NAc cell populations encode ‘liking’ and ‘wanting’ to shape overconsumption remains unclear. Here, we probed the roles of NAc D1 and D2 cells in these processes using cell-specific recording and control in diverse behavioral paradigms that disentangle reward traits of ‘liking’ and ‘wanting’ related to food choice and overeating. NAc D2 cells encoded experience-dependent development of ‘liking’, while NAc D1 cells encoded innate ‘liking’ during the first food taste. Optogenetic control confirmed causal links of D1 and D2 cells to these aspects of ‘liking’. In relation to ‘wanting’, D1 and D2 cells encoded and promoted distinct aspects of food approach: D1 cells interpreted food cues while D2 cells also sustained food-visit-length that facilitates consumption. Finally, at the level of food choice, D1, but not D2, cell activity was sufficient to switch food preference, programming subsequent long-lasting overconsumption. By revealing complementary roles of D1 and D2 cells in consumption, these findings assign neural bases to ‘liking’ and ‘wanting’ in a unifying framework of D1 and D2 cell activity.
Increased neuron density in the midbrain of foveate birds results from profound change in tissue morphogenesis
Authors: Rodrigues Tania , Dib Linda , Bréthaut Émilie , Matter Michel M. , Matter-Sadzinski Lidia , Matter Jean-Marc
Published: October 2022

The increase of brain neuron number in relation with brain size is currently considered to be the major evolutionary path to high cognitive power in amniotes. However, how changes in neuron density did contribute to the evolution of the information-processing capacity of the brain remains unanswered. High neuron densities are seen as the main reason why the fovea located at the optical center of the retina is responsible for sharp vision in birds and primates. The emergence of foveal vision is considered as a breakthrough innovation in visual system evolution. We found that neuron densities in the largest visual center of the midbrain – i.e., the optic tectum – are two to four times higher in modern birds with one or two foveae compared to birds deprived of this specialty. Interspecies comparisons enabled us to identify elements of a hitherto unknown developmental process set up by foveate birds for increasing neuron density in the upper layers of their optic tectum. The late progenitor cells that generate these neurons proliferate in a ventricular zone that can expand only radially. In this particular context, the number of cells in ontogenetic columns increases, thereby setting the conditions for higher cell densities in the upper layers once neurons did migrate.

Graphical Abstract

Highlights

The presence of a fovea is associated with increased neuron density in the optic tectum

Fovea number and deepness influence neuron density in the optic tectum

Increased neuron density in the upper layers of the optic tectum requires major developmental changes

Postponed cell migration, prolonged cell proliferation, hindered tissue growth are necessary settings for achieving high neuron density
Single-domain antibody delivery using an mRNA platform protects against lethal doses of botulinum neurotoxin A
Authors: Panova Eugenia A. , Kleymenov Denis A. , Shcheblyakov Dmitry V. , Bykonia Evgeniia N. , Mazunina Elena P. , Dzharullaeva Alina S. , Zolotar Anastasia N. , Derkaev Artem A. , Esmagambetov Ilias B. , Sorokin Ivan I. , Usachev Evgeny V. , Ivanov Igor A. , Zatsepin Timofei S , Dmitriev Sergey E. , Gushchin Vladimir A. , Logunov Denis Y. , Gintsburg Alexander L.
Published: October 2022

Single-domain antibodies (sdAbs, VHHs, or nanobodies) are a promising tool for the treatment of both infectious and somatic diseases. Their small size greatly simplifies any genetic engineering manipulations. Such antibodies have the ability to bind hard-to-reach antigenic epitopes through long parts of the variable chains, the third complementarity-determining regions (CDR3s). VHH fusion with the canonical immunoglobulin Fc fragment allows the Fc-fusion single-domain antibodies (VHH-Fc) to significantly increase their neutralizing activity and serum half-life. Previously we have developed and characterized VHH-Fc specific to botulinum neurotoxin A (BoNT/A), that showed a 1000-fold higher protective activity than monomeric form when challenged with five times the lethal dose (5 LD50) of BoNT/A. During the COVID-19 pandemic, mRNA vaccines based on lipid nanoparticles (LNP) as a delivery system have become an important translational technology that has significantly accelerated the clinical introduction of mRNA platforms. We have developed an mRNA platform that provides long-term expression after both intramuscular and intravenous application. The platform has been extensively characterized using firefly luciferase (Fluc) as a reporter. An intramuscular administration of LNP-mRNA encoding VHH-Fc antibody made it possible to achieve its rapid expression in mice and resulted in 100% protection when challenged with up to 100 LD50of BoNT/A. The presented approach for the delivery of sdAbs using mRNA technology greatly simplifies drug development for antibody therapy and can be used for emergency prophylaxis.
Effects of inertia and switching costs on customer retention: a study of budget hotels in China
Authors: Li Zhiyong , Long Mang , Huang Songshan (Sam) , Duan Zhaohan , Hu Yingli , Cui Rui
Published: October 2022

Purpose

This paper aims to examine the effect of consumer inertia – a tendency to adhere to prior purchase decisions despite the existence of preferable alternatives – on the relationships between switching costs and customer retention, and explain the controversy within them in the context of budget hotels.

Design/methodology/approach

An empirical test was conducted via structural equation modelling based on 337 self-administered questionnaires from customers at six of Chinese popular budget hotels.

Findings

Consumer inertia was a significant mediator between switching costs and customer retention. Specifically, consumer inertia completely mediated the effects of financial switching costs on customer retention, but partially did between procedural switching costs and customer retention. By introducing consumer inertia, the explanatory power of customer retention improved significantly by 19%.

Originality/value

This paper clarifies the effects of multiple dimensions of switching costs on customer retention via the mediating role of consumer inertia and partly addresses the inconsistency in the prior studies from an inertia perspective.
Efficacy of labile carbon addition to reduce fast‐growing, invasive non‐native plants: A review and meta‐analysis
Authors: Ossanna Lia Q. R. , Gornish Elise S.
Published: October 2022

Elevated soil nitrogen (N) resulting from pollution, fertilizer and woody encroachment in grasslands enhances invasion pressures from weedy plant species. Sawdust, sucrose and other labile carbon (C) sources can be used as a soil amendment to combat the growth of fast‐growing, invasive non‐native plants by immobilizing soil N.

Here, we present a systematic review of 83 publications, and a meta‐analysis from 48 publications. Using hierarchical mixed‐effects meta‐analytic models, we synthesized 655 responses from native plants and 486 responses from non‐native weeds to quantify the overall effect of C addition. We explored the possible explanations for variation in effect, such as differences in study conditions and how C was applied.

Carbon addition studies were almost exclusively reported from the United States, Australia and Canada (93%). The majority of papers (63%) did not include any cost information.

Overall, C addition significantly decreased non‐native weed abundance, but did not significantly affect native plant abundance. A C application rate of at least 210 g C m−2 year−1 (5 Mg sucrose ha−1 year−1 or 4.6 Mg sawdust ha−1 year−1) decreased non‐native weed abundance, but a rate of 2110–3000 g C m−2 year−1 (50–71 Mg sucrose ha−1 year−1 or 46–65 Mg sawdust ha−1 year−1) was required to significantly increase native plant abundance. Carbon addition was most effective in the western USA and southeastern Australia, and when used to suppress non‐native grasses (annual or perennial) and annual forbs. Simultaneous seeding of native species prevented an overall decrease in native plant abundance.

Synthesis and application. When there is a nearby and inexpensive source of C available, we recommend C addition with simultaneous seeding of native species to control invasive non‐native grasses and annual forbs in semi‐arid and arid regions of the western USA and southeast Australia. In contrast to other weed control measures, especially herbicide, C addition does not significantly harm native perennial plants. Future studies should implement longer‐term monitoring, establish larger plots and include cost analysis to improve guidance for land managers.
Improving variant prioritization in exome analysis by entropy‐weighted ensemble of multiple tools
Authors: Fan Yanjie , Zhou Ying , Liu Huili , Luo Xiaomei , Xu Ting , Sun Yu , Yang Tingting , Chen Linlin , Gu Xuefan , Yu Yongguo
Published: October 2022

Variant prioritization is a crucial step in the analysis of exome and genome sequencing. Multiple phenotype‐driven tools have been developed to automate the variant prioritization process, but the efficacy of these tools in clinical setting with fuzzy phenotypic information and whether ensemble of these tools could outperform single algorithm remains to be assessed. A large rare disease cohort with heterogeneous phenotypic information, including a primary cohort of 1614 patients and a replication cohort of 1904 patients referred to exome sequencing, were recruited to assess the efficacy of variant prioritization and their ensemble. Three freely available tools—Exomiser, Xrare, and DeepPVP—and their ensemble were evaluated. The performance of all three tools was influenced by the attributes of phenotypic input. When combining these three tools by weighted‐sum entropy method (EWE3), the ensemble outperformed any single algorithm, achieving a rate of 78% diagnostic variants in top 3 (13% improvement over current best performer, compared to Exomiser: 63%, Xrare: 65%, and DeepPVP: 51%), 88% in top 10 and 96% in top 30. The results were replicated in another independent cohort. Our study supports using entropy‐weighted ensemble of multiple tools to improve variant prioritization and accelerate molecular diagnosis in exome/genome sequencing.