bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidental Finding of Intervertebral Disc Herniation With Increased 18F-FAPI-04 Uptake in a Healthy Volunteer
Authors: Yuan Hui , Liu Entao , Li Zhenxiang , Zhang Qing , Jiang Lei
Published: April 2023

A 44-year-old healthy volunteer received an 18F-FAPI-04 scan for a normal biodistribution and dosimetry study. An incidental finding of an increased uptake of the radiotracer at the L4/5 subarticular disc herniation was noted, and a subsequent MRI scan confirmed the degenerative nature of the lesion.
Factors Affecting Postoperative Complications of Suction-Curettage by Arthroscopic Shaver for Bromhidrosis
Authors: Chen Kun-Han , Changchien Chih-Hsuan , Fang Chien-Liang , Yang Cheng-San , Tsai Chong-Bin , Chen Ming-Shan , Yang Hsin-Yi
Published: April 2023

Background

Suction-curettage by arthroscopic shaver is the most effective treatment for bromhidrosis; however, postoperative complications require wound management and exhibit a high risk of hypertrophic scarring. We investigated factors affecting postoperative complications.

Methods

We retrospectively evaluated data for 215 patients (430 axillae) with bromhidrosis treated with suction-curettage by arthroscopic shaver between 2011 and 2019. Cases followed for less than 1 year were excluded. Complications of hematoma or seroma, epidermis decortication, skin necrosis, and infection were recorded. Multinomial logistic analysis was used to calculate odds ratios and corresponding 95% confidence intervals for the complication of the surgery, adjusting for relevant statistically significant variables.

Results

Complications occurred in 52 axillae (12.1%). Epidermis decortication occurred in 24 axillae (5.6%), with a significant difference for age (P < 0.001). Hematoma occurred in 10 axillae (2.3%) with a significant difference in tumescent infiltration use (P = 0.039). Skin necrosis occurred in 16 axillae (3.7%) with a significant difference for age (P = 0.001). Infection occurred in 2 axillae (0.5%). Severe scarring occurred in 15 axillae (3.5%), with complications related to more severe skin scarring (P < 0.05).

Conclusion

Older age was a risk factor for complications. Use of tumescent infiltration resulted in good postoperative pain control and less hematoma. Patients with complications presented with more severe skin scarring, but none experienced limited range of motion after massage.
Measurement of Frailty
Authors: Perazza Laís R. , Avers Dale , Thompson LaDora V.
Published: April 2023

Frailty is a clinical syndrome observed in older adults that associates with poor health outcomes. Despite the attempt to standardize its definition and clinical features, the complexity and the multiplicity of the physiologic dysregulations observed in frailty have led to the development of innumerous assessment tools. Herein, we highlight frequently used assessment tools for frailty describing the criteria, pros and cons regarding clinical feasibility, reliability, and validity as well as risk predictability. We further compare the 2 well-established landmark frailty assessment tools, the Physical Frailty Phenotype and the Frailty Index, in an attempt to unravel how such distinct methodologies prevail as the most commonly used clinical tools to prevent adverse outcomes worldwide.
Frailty, Meeting Challenges, and Beyond in Geriatric Surgery—10 Years' Experience From Singapore's First Geriatric Surgical Service
Authors: Chia Clement Luck Khng , Yong Nicole Therese Wen Min , Ong Marc Weijie , Lam Xin Yi , Soon Bernice Lip Lin , Tan Kok Yang
Published: April 2023

This article gives an overview of the 10 years' experience of the first dedicated geriatric surgery service in Khoo Teck Puat Hospital, Singapore. Frailty and its adverse impact on emergency and elective surgical procedures are elaborated and strategies to optimize outcomes explained. Via transdisciplinary transinstitutional collaboration, geriatric surgery service instituted trimodal intervention of prehabilitation, nutrition, and psychological support for frail patients, achieved consistent perioperative results, shortened length of hospital stay, and restored baseline function for patients undergoing major elective oncological surgery. Efforts are made to teach transdisciplinary collaboration to the next generation of doctors to meet the challenges of the Era of Geriatric Surgery.
Cognitive Impairment in Liver Transplant Recipients With a History of Cirrhosis: A Systematic Review
Authors: Siddiqui Osama M. , Baskaran Archit B. , Lin Katherine A. , Najam Naela , Shah Tahir , Beestrum Molly L. , Thuluvath Avesh , Bonakdarpour Borna , Kim Minjee , Dietch Zachary , Wolf Michael , Ladner Daniela P.
Published: April 2023

Background.

Cognitive impairment is common among patients with cirrhosis and may persist post-transplantation. This systematic review seeks to (1) describe the prevalence of cognitive impairment in liver transplant (LT) recipients with a history of cirrhosis, (2) describe risk factors for this population, and (3) describe associations between post-transplant cognitive impairment and quality outcome measures.

Methods.

Studies in PubMed, Embase, Scopus, PsychINFO, and the Cochrane Database of Controlled Trials were included through May 2022. Inclusion criteria included (1) population – LT recipient, age ≥18 y, (2) exposure – history of cirrhosis before transplant, and (3) outcome – cognitive impairment after transplant (per validated cognitive testing). Exclusion criteria included (1) wrong study type, (2) abstract-only publication, (3) full-text unavailable, (4) wrong population, (5) wrong exposure, and (6) wrong outcome. The risk of bias was assessed using the Newcastle-Ottawa Scale and the Appraisal tool for Cross-Sectional Studies. The Grading of Recommendations, Assessment, Development, and Evaluations system was used to assess evidence certainty. Data from individual tests were categorized into six cognitive domains: attention, executive function, working memory, long-term memory, visuospatial, and language.

Results.

Twenty-four studies were included covering 847 patients. Follow-up ranged from 1 mo to 1.8 y after LT. Studies had a median of 30 (interquartile range 21.5–50.5) patients. The prevalence of cognitive impairment after LT ranged from 0% to 36%. Forty-three unique cognitive tests were used, the most common being the Psychometric Hepatic Encephalopathy Score. The most frequently assessed cognitive domains were attention (10 studies) and executive function (10 studies).

Conclusions.

The prevalence of cognitive impairment after LT varied across studies depending on cognitive tests utilized and follow-up duration. Attention and executive function were most impacted. Generalizability is limited due to small sample size and heterogeneous methodology. Further studies are needed to examine differences in the prevalence of post-LT cognitive impairment by etiology, risk factors, and ideal cognitive measures.
Diel patterns of fin whale 20 Hz acoustic presence in Eastern Antarctic waters
Authors: Aulich Meghan G. , Miller Brian S. , Samaran Flore , McCauley Robert D. , Saunders Benjamin J. , Erbe Christine
Published: April 2023

This study presents evidence of diel patterns in fin whale (Balaenoptera physalus) 20 Hz acoustic presence in Eastern Antarctic waters. Passive acoustic recordings were collected at four sites in Eastern Antarctica from 2013 to 2019. A generalized linear model fitted by a generalized estimating equation was used to test the hypothesis that fin whale 20 Hz acoustic presence shows significant variation between light regimes dawn, day, dusk and night. In the Indian sector of Antarctica, at the Prydz and Southern Kerguelen Plateau sites, fin whale acoustic presence was significantly more common during the night and dawn before declining during the day and dusk periods. A different diel pattern was observed in the Pacific sector, at the Dumont d'Urville site: fin whale acoustic presence was significantly more common during the day than dusk and night periods. No diel pattern was identified at the Casey site. The identified diel patterns in the Indian sector of Eastern Antarctica correlate with previously identified diel patterns of the fin whales' prey. We suggest an indirect association between fin whale acoustic presence and foraging, with the animals more likely to produce the 20 Hz pulse during the night when not foraging and less likely to vocalize when foraging during the day.
Re-evaluating frontopolar and temporoparietal contributions to detection and discrimination confidence
Authors: Mazor Matan , Gong Chudi , Fleming Stephen M.
Published: April 2023

Previously, we identified a subset of regions where the relation between decision confidence and univariate functional magnetic resonance imaging (fMRI) activity was quadratic, with stronger activation for both high and low compared with intermediate levels of confidence. We further showed that, in a subset of these regions, this quadratic modulation appeared only for confidence in detection decisions about the presence or absence of a stimulus, and not for confidence in discrimination decisions about stimulus identity (Mazoret al.2021). Here, in a pre-registered follow-up experiment, we sought to replicate our original findings and identify the origins of putative detection-specific confidence signals by introducing a novel asymmetric-discrimination condition. The new condition required discriminating two alternatives but was engineered such that the distribution of perceptual evidence was asymmetric, just as in yes/no detection. We successfully replicated the quadratic modulation of subjective confidence in prefrontal, parietal and temporal cortices. However, in contrast with our original report, this quadratic effect was similar in detection and discrimination responses, but stronger in the novel asymmetric-discrimination condition. We interpret our findings as weighing against the detection-specificity of confidence signatures and speculate about possible alternative origins of a quadratic modulation of decision confidence.
Sugiyamaella bielyi f. a., sp. nov. and Sugiyamaella amazoniana f. a., sp. nov., two yeast species isolated from passalid beetles and rotting wood in Amazonia
Authors: Souza Gisele F. L. , Barros Katharina O. , Alvarenga Flávia B. M. , Santos Ana Raquel O. , Fonseca Claúdio R. V. , Abegg Maxwel A. , Lachance Marc-André , Rosa Carlos A.
Published: April 2023

Sixteen yeast isolates representing two novel species of the genus Sugiyamaella were obtained from passalid beetles, their galleries and rotting wood collected in three sites of Amazonian Forest in Brazil. Sequence analyses of the ITS-5.8S region and the D1/D2 domains of the large subunit rRNA gene showed that the first species, described here as Sugiyamaella amazoniana f. a., sp. nov. (holotype CBS 18112, MycoBank 847461) is phylogenetically related to S. bonitensis with these species differing by 37 nucleotide substitutions and six gaps in D1/D2 sequences. S. amazoniana is represented by nine isolates obtained from the guts of the passalid beetles Popilius marginatus, Veturius magdalenae, Veturius sinuosus and Spasalus aquinoi, a beetle gallery and rotting wood. The second species, Sugiyamaella bielyi f. a., sp. nov. (holotype CBS 18148, MycoBank 847463), is most phylogenetically related to several undescribed Sugiyamaella species. S. bielyi is described based on seven isolates obtained from the guts of V. magdalenae and V. sinuosus, a beetle gallery and rotting wood. Both species appear to be associated with passalid beetles and their ecological niches in Amazonian biome.
Tahibacter harae sp. nov., isolated from pig farm soil in Guangdong, PR China
Authors: Chen Haixin , Zhou Yang , Yao Qing , Jiang Hongxia , Zhu Honghui
Published: April 2023

In the process of exploring the microbial diversity of pig farms, a Gram-stain-negative, aerobic, rod-shaped, non-spore-forming, non-motile bacterial strain, designated P2KT, was isolated from soil sample collected at a pig farm, Guangdong Province, PR China. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain P2KT belonged to the genus

Tahibacter

, with the highest sequence similarity to

Tahibacter aquaticus

PYM5-11T (98.6%) and

Tahibacter caeni

BUT-6T (98.3 %). The genome size of strain P2KT was 6.0 Mb with a DNA G+C content of 68.3 mol%. Average nucleotide identity values between strain P2KT and the type strains of the genus

Tahibacter

were 81.1–81.6 %. The digital DNA–DNA hybridization values between P2KT and these relative species were 24.5–25.6%. The polar lipids were phosphatidylethanolamine, phosphatidylglycerol, an unknown aminolipids, two unknown lipids and three unknown phospholipids. The major respiratory quinone of strain P2KT was ubiquinone Q-8, and the main fatty acids (>10.0 % of total fatty acids) of strain P2KT were iso-C15:0, iso-C16:0 and summed feature 9 (C16:0 10-methyl and/or iso-C17:1 ω9c). Based on phenotypic and genotypic data, strain P2KT represents a novel species within the genus

Tahibacter

, for which the name Tahibacter harae sp. nov. is proposed, with the type strain P2KT (=GDMCC 1.3107T=JCM 35231T).
Bivalent mRNA-1273.214 vaccine effectiveness against SARS-CoV-2 omicron XBB* infections
Authors: Chemaitelly Hiam , Ayoub Houssein H. , AlMukdad Sawsan , Faust Jeremy Samuel , Tang Patrick , Coyle Peter , Yassine Hadi M. , Thani Asmaa A. Al , Al-Khatib Hebah A. , Hasan Mohammad R. , Al-Kanaani Zaina , Al-Kuwari Einas , Jeremijenko Andrew , Kaleeckal Anvar H. , Latif Ali N. , Shaik Riyazuddin M. , Abdul-Rahim Hanan F. , Nasrallah Gheyath K. , Al-Kuwari Mohamed G. , Butt Adeel A. , Al-Romaihi Hamad E. , Al-Thani Mohamed H. , Al-Khal Abdullatif , Bertollini Roberto , Abu-Raddad Laith J.
Published: April 2023

Qatar introduced COVID-19 bivalent vaccination for persons ≥12 years old using the 50-μg mRNA-1273.214 vaccine combining SARS-CoV-2 ancestral and omicron BA.1 strains. We estimated effectiveness of this bivalent vaccine against SARS-CoV-2 infection using a matched, retrospective, cohort study. Matched cohorts included 11,482 persons in the bivalent cohort and 56,806 persons in the no-recent-vaccination cohort. During follow-up, 65 infections were recorded in the bivalent cohort and 406 were recorded in the no-recent-vaccination cohort. None progressed to severe, critical, or fatal COVID-19. Cumulative incidence of infection was 0.80% (95% CI: 0.61-1.07%) in the bivalent cohort and 1.00% (95% CI: 0.89-1.11%) in the no-recent- vaccination cohort, 150 days after the start of follow-up. Incidence during follow-up was dominated by omicron XBB* subvariants including XBB, XBB.1, XBB.1.5, XBB.1.9.1, XBB.1.9.2, XBB.1.16, and XBB.2.3. The adjusted hazard ratio comparing incidence of infection in the bivalent cohort to that in the no-recent-vaccination cohort was 0.75 (95% CI: 0.57-0.97). Bivalent vaccine effectiveness against infection was 25.2% (95% CI: 2.6-42.6%). Effectiveness was 21.5% (95% CI: -8.2-43.5%) among persons with no prior infection and 33.3% (95% CI: - 4.6-57.6%) among persons with prior infection. mRNA-1273.214 reduced incidence of SARS- CoV-2 infection, but the protection was modest at only 25%. The modest protection may have risen because of XBB* immune evasion or immune imprinting effects, or combination of both.
Metabolic complexity increases adaptability
Authors: Fritzemeier Claus Jonathan , Ghaffarinasab Sajjad , Lieder Felix , Szappanos Balázs , Jarre Florian , Papp Balázs , Pál Csaba , Lercher Martin J.
Published: April 2023

Bacteria show a striking ability to adapt to new environments through horizontal gene transfer. Anecdotal evidence suggests that some bacteria are more adaptable than others:e.g., intestinalE. colifrequently spin off pathogenic strains adapted to other human tissues, while gastricHelicobacter pylorido not. However, it is unclear what determines the ability of individual strains or species to adapt to new environments. Here, we use pan-genome scale modeling to explore the ability of 102 different unicellular organisms to adapt to each of 5000+ diverse nutritional environments. While the small metabolic systems of specialized endosymbionts typically require 50+ additional metabolic reactions to adapt to new environments, different strains of the generalistE. colirequire on average less than 5 new reactions. Thus, there is a positive feedback between metabolic complexity and adaptability, contrary to speculations that complex systems are generally less adaptable.
Female reed warblers in social pairs with low MHC dissimilarity achieve higher MHC compatibility through random extra-pair matings
Authors: Halupka Lucyna , O’Connor Emily , Strandh Maria , Sztwiertnia Hanna , Klimczuk Ewelina , Hasselquist Dennis , Westerdahl Helena
Published: April 2023

Major Histocompatibility Complex (MHC) polymorphism is maintained by balancing selection through host-pathogen interactions and mate choice. MHC-based mate choice has been proposed across a wide range of vertebrates. However, the likelihood of its existence in songbirds has been questioned because of their poorly developed olfactory sense, which is a trait considered crucial in pre-copulatory mate choice to determine both own MHC and the MHC of putative partners. In this study, we show that female reed warblers,Acrocephalus scirpaceus, with extra-pair young in their nests have a lower MHC class I (MHC-I) dissimilarity with their social mate than females without extra-pair young in their nests. We also show that the MHC-I dissimilarity of successfully siring extra-pair males is not different from that of either the other males with territories surrounding the social nest (i.e.putative extra-pair males) or the pairs without extra-pair young in their nests. Taken together with the observation that extra-pair mating in reed warblers is common, we argue that these results support a scenario where extra-pair mating is more likely to lead to successful fertilisation when there is a high similarity in MHC-I between the female and her social male. Furthermore, as our data suggest that extra-pair mating at random can result in a higher MHC-I dissimilarity this scenario does not require any active female mate choice for MHC-I dissimilar males to drive this pattern.
Dynamic Entrainment: A deep learning and data-driven process approach for synchronization in the Hodgkin-Huxley model
Authors: Saghafi Soheil , Sanaei Pejman
Published: April 2023

Resonance and synchronized rhythm are important phenomena and can be either constructive or destructive in dynamical systems in the nature, specifically in biology. There are many examples showing that the human’s body organs must maintain their rhythm in order to function properly. For instance, in the brain, synchronized or desynchronized electrical activities can lead to neurodegenerative disorders such as Huntington’s disease. In this paper, we adopt a well known conductance based neuronal model known as Hodgkin-Huxley model describing the propagation of action potentials in neurons. Armed with the “data-driven” process alongside the outputs of the Hodgkin-Huxley model, we introduce a novelDynamic Entrainmenttechnique, which is able to maintain the system to be in its entrainment regime dynamically by applying deep learning approaches.
In VitroModeling of CD8 T Cell Exhaustion Enables CRISPR Screening to Reveal a Role for BHLHE40
Authors: Wu Jennifer E. , Manne Sasikanth , Ngiow Shin Foong , Baxter Amy E. , Huang Hua , Freilich Elizabeth , Clark Megan L. , Lee Joanna H. , Chen Zeyu , Khan Omar , Staupe Ryan P. , Huang Yinghui J. , Shi Junwei , Giles Josephine R. , Wherry E. John
Published: April 2023

Identifying novel molecular mechanisms of exhausted CD8 T cells (Tex) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation ofin vivoTexcan be costly and inefficient.In vitromodels of Texare easily customizable and quickly generate high cellular yield, offering an opportunity to perform CRISPR screening and other high-throughput assays. We established anin vitromodel of chronic stimulation and benchmarked key phenotypic, functional, transcriptional, and epigenetic features against bona fidein vivoTex. We leveraged this model ofin vitrochronic stimulation in combination with pooled CRISPR screening to uncover transcriptional regulators of T cell exhaustion. This approach identified several transcription factors, including BHLHE40.In vitroandin vivovalidation defined a role for BHLHE40 in regulating a key differentiation checkpoint between progenitor and intermediate subsets of Tex. By developing and benchmarking anin vitromodel of Tex, we demonstrate the utility of mechanistically annotatedin vitromodels of Tex, in combination with high-throughput approaches, as a discovery pipeline to uncover novel Texbiology.
A biophysical rationale for the selective inhibition of PTP1B over TCPTP by nonpolar terpenoids
Authors: Friedman Anika J. , Padgette Hannah M. , Kramer Levi , Liechty Evan T. , Donovan Gregory W. , Fox Jerome M. , Shirts Michael R.
Published: April 2023

Protein tyrosine phosphatases (PTPs) are emerging drug targets for many diseases, including type 2 diabetes, obesity, and cancer. However, a high degree of structural similarity between the catalytic domains of these enzymes has made the development of selective pharmacological inhibitors an enormous challenge. Our previous research uncovered two unfunctionalized terpenoid inhibitors that selectively inhibit PTP1B over TCPTP, two PTPs with high sequence conservation. Here, we use molecular modeling with experimental validation to study the molecular basis of this unusual selectivity. Molecular dynamics (MD) simulations indicate that PTP1B and TCPTP contain a conserved h-bond network that connects the active site to a distal allosteric pocket; this network stabilizes the closed conformation of the catalytically influential WPD loop, which it links to the L–11 loop andα3 andα7 helices—the C-terminal side of the catalytic domain. Terpenoid binding to either of two proximal allosteric sites—anαsite and aβsite—can disrupt the allosteric network. Interestingly, binding to theαsite forms a stable complex with only PTP1B; in TCPTP, where two charged residues disfavor binding at theαsite, the terpenoids bind to theβsite, which is conserved between the two proteins. Our findings indicate that minor amino acid differences at the poorly conservedαsite enable selective binding, a property that might be enhanced with chemical elaboration, and illustrate, more broadly, how minor differences in the conservation of neighboring—yet functionally similar—allosteric sites can have very different implications for inhibitor selectivity.
Computational design of non-porous, pH-responsive antibody nanoparticles
Authors: Yang Erin C. , Divine Robby , Miranda Marcos C. , Borst Andrew J. , Sheffler Will , Zhang Jason Z , Decarreau Justin , Saragovi Amijai , Abedi Mohamad , Goldbach Nicolas , Ahlrichs Maggie , Dobbins Craig , Hand Alexis , Cheng Suna , Lamb Mila , Levine Paul M. , Chan Sidney , Skotheim Rebecca , Fallas Jorge , Ueda George , Lubner Joshua , Somiya Masaharu , Khmelinskaia Alena , King Neil P. , Baker David
Published: April 2023

Programming protein nanomaterials to respond to changes in environmental conditions is a current challenge for protein design and important for targeted delivery of biologics. We describe the design of octahedral non-porous nanoparticles with the three symmetry axes (four-fold, three-fold, and two-fold) occupied by three distinct protein homooligomers: ade novodesigned tetramer, an antibody of interest, and a designed trimer programmed to disassemble below a tunable pH transition point. The nanoparticles assemble cooperatively from independently purified components, and a cryo-EM density map reveals that the structure is very close to the computational design model. The designed nanoparticles can package a variety of molecular payloads, are endocytosed following antibody-mediated targeting of cell surface receptors, and undergo tunable pH-dependent disassembly at pH values ranging between to 5.9-6.7. To our knowledge, these are the first designed nanoparticles with more than two structural components and with finely tunable environmental sensitivity, and they provide new routes to antibody-directed targeted delivery.
Genetic drift and genome reduction in the plant pathogenCandidatusLiberibacter solanacearum shapes a new enzyme in lysine biosynthesis
Authors: Gilkes Jenna M. , Frampton Rebekah A. , Board Amanda J. , Hudson André O. , G. Price Thomas , Crittenden Deborah L. , Muscroft-Taylor Andrew C. , Sheen Campbell R. , Smith Grant R. , Dobson Renwick C.J.
Published: April 2023

The effect of population bottlenecks and genome reduction on enzyme function is poorly understood. ‘CandidatusLiberibacter solanacearum’ is a bacterium with a reduced genome that is transmitted vertically to the egg of an infected psyllid—a population bottleneck that imposes genetic drift and is predicted to affect protein structure and function. Here, we define the effects of genome reduction and genetic drift on the function ofCa. L. solanacearum dihydrodipicolinate synthase (CLsoDHDPS), which catalyses the committed branchpoint reaction in diaminopimelate and lysine biosynthesis. We demonstrate thatCLsoDHDPS is expressed inCa. L. solanacearum and expression is increased ∼2-fold in the insect host compared toin planta.CLsoDHDPS has increased aggregation propensity, implying mutations have destabilised the enzyme but are compensated for through elevated chaperone expression and a stabilised oligomeric state.CLsoDHDPS uses a ternary-complex kinetic mechanism, which is unique among DHDPS enzymes, has unusually low catalytic ability, but an unusually high substrate affinity. Structural studies demonstrate that the active site is more open, and the structure ofCLsoDHDPS with both pyruvate and the substrate analogue succinic-semialdehyde reveals that the product is both structurally and energetically different and therefore evolution has in this case fashioned a new enzyme. Our study reveals the effects of genome reduction and genetic drift on the function of essential enzymes and provides insights on bacteria-host co-evolutionary association. We suggest that bacteria with endosymbiotic lifestyles present a rich vein of interesting enzymes useful for understanding enzyme function and/or informing protein engineering efforts.
Transcriptomics and Metabolomics Reveal Tomato Consumption Alters Hepatic Xenobiotic Metabolism and Induces Steroidal Alkaloid Metabolite Accumulation in Mice
Authors: Dzakovich Michael P. , Goggans Mallory L. , Thomas-Ahner Jennifer M. , Moran Nancy E. , Clinton Steven K. , Francis David M. , Cooperstone Jessica L.
Published: April 2023

Scope

Tomato consumption is associated with many health benefits including lowered risk for developing certain cancers. It is hypothesized that tomato phytochemicals are transported to the liver and other tissues where they alter gene expression in ways that lead to favorable health outcomes. However, the effects of tomato consumption on mammalian liver gene expression and chemical profile are not well defined.

Methods and results

We hypothesized that tomato consumption would alter mouse liver transcriptomes and metabolomes compared to a control diet. C57BL/6 mice (n=11-12/group) were fed a macronutrient matched diet containing either 10% red tomato, 10% tangerine tomato, or no tomato powder for 6 weeks after weaning. RNA-Seq followed by gene set enrichment analyses indicated that tomato type and consumption, in general, altered expression of phase I and II xenobiotic metabolism genes. Untargeted metabolomics experiments revealed distinct clustering between control and tomato fed animals. Nineteen molecular formulas (representing 75 chemical features) were identified or tentatively identified as steroidal alkaloids and isomers of their phase I and II metabolites; many of which are reported for the first time in mammals.

Conclusion

These data together suggest tomato consumption may impart benefits partly through enhancing detoxification potential.
Normalization in mouse primary visual cortex
Authors: Zayyad Zaina A. , Maunsell John H. R. , MacLean Jason N.
Published: April 2023

When multiple stimuli appear together in the receptive field of a visual cortical neuron, the response is typically close to the average of that neuron’s response to each individual stimulus. The departure from a linear sum of each individual response is referred to as normalization. In mammals, normalization has been best characterized in the visual cortex of macaques and cats. Here we study visually evoked normalization in the visual cortex of awake mice using optical imaging of calcium indicators in large populations of layer 2/3 (L2/3) V1 excitatory neurons and electrophysiological recordings across layers in V1. Regardless of recording method, mouse visual cortical neurons exhibit normalization to varying degrees. The distributions of normalization strength are similar to those described in cats and macaques, albeit slightly weaker on average.
Conserved Metabolic Regulator ArcA Responds to Oxygen Availability, Iron Limitation, and Cell Envelope Perturbations during Bacteremia
Authors: Brown Aric N. , Anderson Mark T. , Smith Sara N. , Bachman Michael A. , Mobley Harry L. T.
Published: April 2023

Bacteremia, a systemic infection associated with severe clinical outcomes, is often caused by Gram-negative facultative anaerobes. ArcAB, a two-component regulatory system that represses aerobic respiration, is a key mediator of metabolic adaptation for such bacteria. Using targeted mutational analysis informed by global genetic screens, we identified thearcAgene as promoting fitness ofKlebsiella pneumoniae,Citrobacter freundii, andSerratia marcescensbut notEscherichia coliin a murine model of bacteremia. Engineered mutants lackingarcAexhibit a dysregulated response to changes in oxygen availability, iron limitation, and membrane perturbations, all of which bacterial cells experience during infection. The genetic response of thearcAmutants relative to wild-type strains to the cationic antimicrobial peptide polymyxin B demonstrates an expanded role for ArcA as an activator in response to membrane damage in addition to metabolic adaptation. ArcA function is furthermore linked to electron transport chain activity based on its response to uncoupling of proton motive force by carbonyl cyanide-m-chlorophenylhydrazone (CCCP). Differences in lactate and acetate levels as well as lactate dehydrogenase activity betweenarcAmutant and wild-type cells following CCCP treatment establish an ArcA-mediated shift to fermentation independent of oxygen availability. This study highlights the semi-conserved role of ArcA during bacteremia and consolidates infection phenotypes into a comprehensive model based on respiratory activity.

AUTHOR SUMMARY

Infections of the bloodstream are life-threatening and can result in sepsis, an overreaction of the host immune system that ultimately damages the body. Gram-negative bacteria are responsible for causing many cases of bloodstream infections, also referred to as bacteremia. The long-term goal of our work is to understand how these bacteria establish and maintain infection during bacteremia. We have previously identified the transcription factor ArcA, which promotes fermentation in bacteria, as a likely contributor to the growth and survival of bacteria in this environment. Here, we study ArcA in the Gram-negative speciesCitrobacter freundii,Klebsiella pneumoniae,andSerratia marcescens.Our findings aid in determining how these bacteria sense their environment, utilize nutrients, and generate energy while also countering attacks from the host immune system. This information is critical for developing better models of infection to inform future therapeutic development.
In Vivo mRNA Hacking with Staple Oligomers Prevents Myocardial Hypertrophy
Authors: Katsuda Yousuke , Kamura Takuto , Kida Tomoki , Saeki Takeru , Itsuki Yua , Kato Yuri , Nakamura Taishi , Nishida Motohiro , Kitamura Yusuke , Ihara Toshihiro , Hagihara Masaki , Sato Shin-ichi
Published: April 2023

Summary paragraph

The elucidation of gene-silencing mechanisms by RNA interference (RNAi) and antisense oligomers has drawn increasing attention to nucleic acid medicine. However, several challenges remain to be overcome, such as in vivo stability1, target selectivity2,3, drug delivery4,5, and induced innate immunity6. Here, we report a new, versatile, and highly-selective method to hack RNA by controlling RNA structure using short oligonucleotides (RNA hacking: RNAh) in living cells. The oligonucleotide, named Staple oligomer, hybridizes specifically to a target mRNA and artificially induces an RNA higher-order structure, RNA G-quadruplex (RGq)7, on the mRNA. As a result, the RGq allows effective suppression of the target protein translation. This technology does not require cooperation with bioprocesses including enzymatic reactions as in RNAi or antisense technologies, permitting the introduction of artificial nucleic acids into Staple oligomers to increase their in vivo stability without compromising their effectiveness. The method was validated by translational regulation of the mRNAs of TPM3, MYD88, and TRPC6, in a cell-free system and in living mammalian cells. In vivo application of the technology to TRPC6 mRNA allowed us to prevent cardiac hypertrophy in transverse aortic constriction (TAC)-treated mice with no detectable off-target effects. This technology provides new insights into gene therapy after RNAi and antisense technologies.
Assembling membraneless organelles fromde novodesigned proteins
Authors: Hilditch Alexander T. , Romanyuk Andrey , Cross Stephen J. , Obexer Richard , McManus Jennifer J. , Woolfson Derek N.
Published: April 2023

Recent advances inde novoprotein design have delivered a diversity of discretede novoprotein structures and complexes. A new challenge for the field is to use these designs directly in cells to intervene in biological process and augment natural systems. The bottom-up design of self-assembled objects like microcompartments and membraneless organelles is one such challenge, which also presents opportunities for chemical and synthetic biology. Here, we describe the design of genetically encoded polypeptides that form membraneless organelles inEscherichia coli(E. coli). To do this, we combinede novoα-helical sequences, intrinsically disordered linkers, and client proteins in single-polypeptide constructs. We tailor the properties of the helical regions to shift protein assembly from diffusion-limited assemblies to dynamic condensates. The designs are characterised in cells andin vitrousing biophysical and soft-matter physics methods. Finally, we use the designed polypeptide to co-compartmentalise a functional enzyme pair inE. coli.
P2X7-dependent exchange of extracellular microparticles and mitochondria by mouse microglia
Authors: Falzoni Simonetta , Chiozzi Paola , Vultaggio-Poma Valentina , Tarantini Mario , Adinolfi Elena , Boldrini Paola , Giuliani Anna Lisa , Gorecki Dariusz C. , Virgilio Francesco Di
Published: April 2023

Microparticles (MPs) are ubiquitously secreted by all cells and play a fundamental role in numerous biological processes such as cell-to-cell communication, cell differentiation, inflammation, and cell energy transfer. Ligation of the P2X7 receptor (P2X7R) by extracellular ATP (eATP) is the well-known stimulus for MP release, which affects their contents in a cell-specific fashion. We investigated MP release and functional impact in mouse microglial cell lines characterized for high (N13-P2X7RHigh) or low (N13-P2X7RLow) expression of the P2X7R. Stimulation with extracellular ATP triggered a P2X7R-dependent release of a MP population enriched with naked mitochondria. Released mitochondria were taken up and incorporated into the mitochondrial network of the recipient cells in a P2X7R-dependent fashion. Other constituents of the MP cargo, e.g. NLRP3 and the P2X7R itself, were also delivered to the recipient cells. Transfer of mitochondria, NLRP3 and P2X7R increased the energy level of the recipient cells and conferred a pro-inflammatory phenotype. These data show that P2X7R-dependent exchange of MPs and mitochondria modulates energy metabolism and inflammatory responses, pointing to the P2X7R as a master regulator of intercellular organelle and MP trafficking in mouse microglia.
cAMP binding to closed pacemaker ion channels is cooperative
Authors: Kuschke Stefan , Thon Susanne , Schwabe Tina , Benndorf Klaus , Schmauder Ralf
Published: April 2023

Most of receptor proteins in biomembranes are oligomers of either homologue or identical subunits, that govern a cooperative activation process. HCN ion channels, generating electric rhythmicity in specialized brain neurons and cardiomyocytes1, are tetramers activated by hyperpolarizing voltage and modulated by the intracellular binding of the second messenger cAMP2,3. The molecular processes underlying the cooperative action of the subunits4-6by the binding are not fully understood, in particular if they are necessarily associated with channel activation7or not, as recently reported for detergent-solubilized receptors positioned in zero-mode waveguides8. Here we show positive cooperativity in ligand binding to resting HCN2 channels in native cell membranes by analyzing the binding of fluorescence-labelled single cAMP derivatives to the channels. Kinetic modelling reveals, that the affinity of the still empty binding sites rises with increased degree of occupation and that the transition of the channel to a flip state is promoted accordingly. We conclude that ligand binding to the subunits in resting HCN2 channels is already cooperative prior to channel activation. This shows that single-molecule binding studies can quantify cooperativity in ligand binding to receptors in native membranes based on equilibrium measurements.
Measuring the perception and metacognition of time
Authors: Cropper Simon J , Little Daniel R , Xu Liheng , Bruno Aurelio M , Johnston Alan
Published: April 2023

The ability of humans to identify and reproduce short time intervals (in the region of a second) may be affected by many factors ranging from the gender of the individual observer, through the attentional state, to the precise spatiotemporal structure of the stimulus. The relative roles of these very different factors are a challenge to describe and define; several methodological approaches have been used to achieve this to varying degrees of success. Here we describe a new paradigm affording not only a first-order measurement of the perceived duration of an interval but also a second-order metacognitive judgement of perceived time. This approach, we argue, expands the form of the data generally collected in duration-judgements and allows more detailed comparison of psychophysical behaviour to the underlying theory. We also describe a measurement model which provides estimates of the variability of the temporal estimates and the metacognitive judgments allowing comparison to an ideal observer. We fit the model to data collected for judgements of 750ms (bisecting 1500ms) and 1500ms (bisecting 3000ms) intervals across three stimulus modalities (Visual, Audio & Audiovisual). This enhanced form of data on a given interval judgement and the ability to track its progression on a trial-by-trial basis offers a way of looking at the different roles that subject-based, task-based and stimulus-based factors have on the perception of time.
Reduction in mRNA expression of the neutrophil chemoattract factor CXCL1 inPseudomonas aeruginosatreated Barth Syndrome B lymphoblasts
Authors: Zegallai Hana M. , Duan Kangmin , Hatch Grant M.
Published: April 2023

Barth Syndrome (BTHS) is a rare X-linked genetic disease caused by a mutation inTAFAZZIN, a cardiolipin transacylase. Approximately 70% of patients with BTHS exhibit severe infections due to neutropenia. However, neutrophils from BTHS patients have been shown to exhibit normal phagocytosis and killing activity. B lymphocytes play a crucial role in the regulation of the immune system and when activated secret cytokines known to attract neutrophils to sites of infection. We examined expression of chemokine (C-X-C motif) ligand 1 (CXCL1), a known chemotactic for neutrophils, in Epstein-Barr virus transformed control and BTHS B lymphoblasts. Age-matched control and BTHS B lymphoblasts were incubated withPseudomonas aeruginosafor 24 h and then cell viability, CD27+, CD24+, CD38+, CD138+ and PD1+ surface marker expression and CXCL1 mRNA expression determined. Cell viability was maintained in lymphoblasts incubated with a ratio of 50:1 bacteria:B cells. Surface marker expression was unaltered between control and BTHS B lymphoblasts. In contrast, CXCL1 mRNA expression was reduced approximately 90% (p<0.05) in untreated BTHS B lymphoblasts compared to control cells and approximately 70% (p<0.05) in bacterial treated BTHS B lymphoblasts compared to control cells. Thus, naïve and bacterial-activated BTHS B lymphoblasts exhibit reduced mRNA expression of the neutrophil chemoattractant factor CXCL1. We suggest that impaired bacterial activation of B cells in some BTHS patients could promote immune dysfunction, and this may contribute to infections.
Gas diffusion kinetics drive embolism spread in angiosperm xylem: evidence from flow-centrifuge experiments and modelling
Authors: Silva Luciano M. , Pereira Luciano , Kaack Lucian , Guan Xinyi , Trabi Christophe L. , Jansen Steven
Published: April 2023

Understanding xylem embolism formation is challenging due to dynamic changes and multiphase interactions in conduits. If embolism spread involves gas movement in xylem, we hypothesise that it is affected by time. We measured hydraulic conductivity (Kh) in flow-centrifuge experiments over one hour at a given pressure and temperature for stem samples of three angiosperm species. Temporal changes in Khat 5, 22, and 35°C, and at various pressures were compared to modelled gas pressure changes in a recently embolised vessel in the centre of a centrifuge sample. Temporal changes in Khat 22°C showed maximum relative increases between 6% and 40%, and maximum decreases between 41% and 61% at low and high centrifugal speed, respectively. Logarithmic changes in Khwere species-specific, and most pronounced during the first 15 minutes. Embolism formation started near the edges of centrifuge samples and gradually increased at the centre. Moreover, measured decreases in Khstrongly correlated with modelled increases in gas concentration in a recently embolised vessel. Although embolism is mostly pressure-driven, our experimental and modelled data indicate that time, conduit characteristics, and temperature are involved due to their role in gas diffusion. Gas diffusion, however, does not cover the entire process of embolism spread.
A conserved extracellular ribonuclease with broad-spectrum cytotoxic activity enables smut fungi to compete with host-associated bacteria
Authors: Ökmen Bilal , Katzy Philipp , Wemhöner Raphael , Doehlemann Gunther
Published: April 2023

Ribotoxins are secreted ribonucleases that specifically target and cleave the universally conserved sarcin-ricin loop sequence of rRNA, which leads to inhibition of protein biosynthesis and subsequently to cell death. We have identified and characterized a secreted Ribo1 protein of plant pathogenic smut fungi. Heterologous expression in different model systems showed that smut Ribo1 has cytotoxic activity against bacteria, yeast, host and non-host plants. Recombinant expression of Ribo1 inNicotiana benthamianainduced plant cell death; however, an active site mutant induced cell death only when expressed as a secreted protein. In the maize smutUstilago maydis, transcription ofRibo1is specifically induced in early infection stages. While a knock-out mutant revealed that Ribo1 is dispensable forU. maydisvirulence, the overexpression of Ribo1in-plantahad a strong dominant negative effect on virulence and induced host defense responses including cell death. This suggests a function of Ribo1 during the epiphytic development rather than for invasive colonization of the host. Accordingly, in presence of the biocontrol bacteriaPantoeasp., which were isolated from maize leaves, theribo1knock-out mutant was significantly impaired in virulence. Together, we conclude that Ribo1 enables smut fungi to compete with host-associated bacteria during epiphytic development.
Root barrier surveillance mechanisms convey soil nitrogen status to shoots
Authors: Shen Defeng , Wippel Kathrin , Remmel Simone , Zhang Pengfan , Kuertoes Noah , Neumann Ulla , Kopriva Stanislav , Andersen Tonni Grube
Published: April 2023

In roots, formation of the Casparian strip in the endodermal cell walls provides a mechanism for selective uptake of nutrients and water. Establishment of this filter is under spatial surveillance by a receptor-ligand mechanism termed the Schengen pathway. This system provides a mechanism to initiate downstream signaling responses in case of dysfunctional barrier establishment. Due to this interconnected nature, the endogenous physiological role of this survaillance mechanism remain difficult to untangle from the direct barrier function. This is in particularly evident in complex growth setups where multiple inputs are integrated into general whole-plant responses. In this work, we address this by rewiring the genetic network that underlies root barrier formation. We create plants with enhanced, Schengen-independent Casparian strip formation that are not only suitable to probe the role of stronger barrier establishment, but also to evaluate the associated signaling output independently. With focus on the latter, we subjected the rewired plants, as well as a number of established barrier mutants, to multifaceted growth conditions including nitrogen fertilized agricultural soil conditions. By profiling their above- and belowground (a)biotic responses our work reveals that, while increased Casparian strip formation mainly provides the plant with an improved stress resistance, the Schengen pathway is necessary for establishment of a growth-promoting root microbiome and serves to convey information of soil nitrogen status to the shoot. This identifies the Schengen pathway as an essential receptor-based signaling hub for adaptive integration of barrier status, nutritional responses and (a)biotic signaling between above- and belowground tissues.
A minimal physical model for curvotaxis driven by curved protein complexes at the cell’s leading edge
Authors: Sadhu Raj Kumar , Luciano Marine , Xi Wang , Martinez-Torres Cristina , Schröder Marcel , Blum Christoph , Tarantola Marco , Penič Samo , Iglič Aleš , Beta Carsten , Steinbock Oliver , Bodenschatz Eberhard , Ladoux Benoît , Gabriele Sylvain , Gov Nir S.
Published: April 2023

Cells often migrate on curved surfaces inside the body, such as curved tissues, blood vessels or highly curved protrusions of other cells. Recentin-vitroexperiments provide clear evidence that motile cells are affected by the curvature of the substrate on which they migrate, preferring certain curvatures to others, termed “curvotaxis”. The origin and underlying mechanism that gives rise to this curvature sensitivity are not well understood. Here, we employ a “minimal cell” model which is composed of a vesicle that contains curved membrane protein complexes, that exert protrusive forces on the membrane (representing the pressure due to actin polymerization). This minimal-cell model gives rise to spontaneous emergence of a motile phenotype, driven by a lamellipodia-like leading edge. By systematically screening the behaviour of this model on different types of curved substrates (sinusoidal, cylinder and tube), we show that minimal ingredients and energy terms capture the experimental data. The model recovers the observed migration on the sinusoidal substrate, where cells move along the grooves (minima), while avoiding motion along the ridges. In addition, the model predicts the tendency of cells to migrate circumferentially on convex substrates and axially on concave ones. Both of these predictions are verified experimentally, on several cell types. Altogether, our results identify the minimization of membrane-substrate adhesion energy and binding energy between the membrane protein complexes as key players of curvotaxis in cell migration.