bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors associated with MRI success in children cooled for neonatal encephalopathy and controls
Authors: Woodward Kathryn , Spencer Arthur P. C. , Jary Sally , Chakkarapani Ela
Published: July 2022

Objective

To investigate if an association exists between motion artefacts on brain MRI and comprehension, co-ordination, or hyperactivity scores in children aged 6–8 years, cooled for neonatal encephalopathy (cases) and controls.

Methods

Case children (n = 50) without cerebral palsy were matched with 43 controls for age, sex, and socioeconomic status. Children underwent T1-weighted (T1w), diffusion-weighted image (DWI) brain MRI and cognitive, behavioural, and motor skills assessment. Stepwise multivariable logistic regression assessed associations between unsuccessful MRI and comprehension (including Weschler Intelligence Scale for Children (WISC-IV) verbal comprehension, working memory, processing speed and full-scale IQ), co-ordination (including Movement Assessment Battery for Children (MABC-2) balance, manual dexterity, aiming and catching, and total scores) and hyperactivity (including Strengths and Difficulties Questionnaire (SDQ) hyperactivity and total difficulties scores).

Results

Cases had lower odds of completing both T1w and DWIs (OR: 0.31, 95% CI 0.11–0.89). After adjusting for case-status and sex, lower MABC-2 balance score predicted unsuccessful T1w MRI (OR: 0.81, 95% CI 0.67–0.97,p = 0.022). Processing speed was negatively correlated with relative motion on DWI (r = −0.25,p = 0.026) and SDQ total difficulties score was lower for children with successful MRIs (p = 0.049).

Conclusions

Motion artefacts on brain MRI in early school-age children are related to the developmental profile.

Impact

Children who had moderate/severe neonatal encephalopathy are less likely to have successful MRI scans than matched controls.

Motion artefact on MRI is associated with lower MABC-2 balance scores in both children who received therapeutic hypothermia for neonatal encephalopathy and matched controls, after controlling for case-status and sex.

Exclusion of children with motion artefacts on brain MRI can introduce sampling bias, which impacts the utility of neuroimaging to understand the brain–behaviour relationship in children with functional impairments.
Fathers’ sensitive parenting enhanced by prenatal video-feedback: a randomized controlled trial using ultrasound imaging
Authors: Buisman Renate S. M. , Alyousefi-van Dijk Kim , de Waal Noor , Kesarlal Ashwina R. , Verhees Martine W. F. T. , van IJzendoorn Marinus H. , Bakermans-Kranenburg Marian J.
Published: July 2022

Background

The aim of this study was to evaluate an interaction-based prenatal parenting intervention program aimed at promoting parental sensitivity and involvement in expectant fathers using ultrasound images: Prenatal Video-Feedback Intervention to Promote Positive Parenting (VIPP-PRE).

Methods

In this randomized controlled trial, 73 first-time, healthy expectant fathers were enrolled. Participants were randomly assigned to the VIPP-PRE intervention (n = 39) or a dummy intervention (n = 34). Parental sensitivity was coded from video-recorded 10-min interactions with an infant simulator at a prenatal pretest and with fathers’ own infant at a postnatal posttest. Prenatal and postnatal involvement was assessed via an application on participants’ smartphones.

Results

Fathers receiving VIPP-PRE demonstrated increased sensitivity across the perinatal period, relative to fathers receiving a dummy intervention. Fathers’ involvement with the infant increased significantly from the prenatal to postnatal period, regardless of the intervention.

Conclusions

Prenatal video-feedback using ultrasound imaging of the unborn child has the potential to promote the quality of parenting in an important, but understudied, population and period: men in the transition to fatherhood. Future research should examine the long-term effectiveness of VIPP-PRE and its effectiveness in increasing parenting quality in at-risk families.

Impact

This study identifies a brief and focused prenatal intervention using assisted interactions between the father and his baby by means of ultrasound imaging as a promising strategy to improve sensitive fathering in the early postnatal phase.

Our study shows that pregnancy provides a window of opportunity for promoting prenatal involvement and bonding in expectant fathers, with potential long-term benefits for the future father–child relationship.

Ultrasound measures are currently used to monitor fetal growth and development, but our results suggest that they may also create an opportunity for stimulating father–infant interaction to promote postnatal caregiving quality.
Using machine learning to impact on long-term clinical care: principles, challenges, and practicalities
Authors: Ashton James J. , Young Aneurin , Johnson Mark J. , Beattie R. Mark
Published: July 2022

The rise of machine learning in healthcare has significant implications for paediatrics. Long-term conditions with significant disease heterogeneity comprise large portions of the routine work performed by paediatricians. Improving outcomes through discovery of disease and treatment prediction models, alongside novel subgroup clustering of patients, are some of the areas in which machine learning holds significant promise. While artificial intelligence has percolated into routine use in our day to day lives through advertising algorithms, song or movie selections and sifting of spam emails, the ability of machine learning to utilise highly complex and dimensional data has not yet reached its full potential in healthcare. In this review article, we discuss some of the foundations of machine learning, including some of the basic algorithms. We emphasise the importance of correct utilisation of machine learning, including adequate data preparation and external validation. Using nutrition in preterm infants and paediatric inflammatory bowel disease as examples, we discuss the evidence and potential utility of machine learning in paediatrics. Finally, we review some of the future applications, alongside challenges and ethical considerations related to application of artificial intelligence.

Impact

Machine learning is a widely used term; however, understanding of the process and application to healthcare is lacking.

This article uses clinical examples to explore complex machine learning terms and algorithms.

We discuss limitations and potential future applications within paediatrics and neonatal medicine.
Mesenchymal stem cell therapy in perinatal arterial ischemic stroke: systematic review of preclinical studies
Authors: Lehnerer Verena , Roidl Anna , Romantsik Olga , Guzman Raphael , Wellmann Sven , Bruschettini Matteo
Published: July 2022

Background

Perinatal arterial ischemic stroke (PAIS) is a neurologic disorder leading to long-term complications. Mesenchymal stem cells (MSCs) have emerged as a novel therapeutic agent. This systematic review aims to determine the effects of stem cell-based interventions for the treatment of PAIS in preclinical studies.

Methods

We included all controlled studies on MSCs in neonatal animals with PAIS. Functional outcome was the primary outcome. The literature search was performed in February 2021.

Results

In the 20 included studies, MSCs were most frequently delivered via intracerebral injection (n = 9), 3 days after the induction of PAIS (n = 8), at a dose ranging from 5 × 104 to 5 × 106 cells. The meta-analysis showed an improvement on the cylinder rearing test (MD: −10.62; 95% CI: −14.38 to −6.86) and on the water maze test (MD: 1.31 MD; 95% CI: 0.80 to 1.81) in animals treated with MSCs compared to the control group animals.

Conclusion

MSCs appear to improve sensorimotor and cognitive performance in PAIS-injured animals; however, the certainty of the evidence is low. Registration of the protocol of preclinical studies, appropriate sample size calculation, rigorous randomization, and reporting of the data on animal sex and survival are warranted.

PROSPERO registration number: CRD42021239642.

Impact

This is the first systematic review and meta-analysis of preclinical studies investigating the effects of MSCs in an experimental model of PAIS.

MSCs appear to improve sensorimotor and cognitive performance in PAIS-injured neonatal animals.

The certainty of the evidence is low due to high or unclear risk of bias in most domains.
Functional isolation, culture and cryopreservation of adult human primary cardiomyocytes
Authors: Zhou Bingying , Shi Xun , Tang Xiaoli , Zhao Quanyi , Wang Le , Yao Fang , Hou Yongfeng , Wang Xianqiang , Feng Wei , Wang Liqing , Sun Xiaogang , Wang Li , Hu Shengshou
Published: July 2022

Cardiovascular diseases are the most common cause of death globally. Accurately modeling cardiac homeostasis, dysfunction, and drug response lies at the heart of cardiac research. Adult human primary cardiomyocytes (hPCMs) are a promising cellular model, but unstable isolation efficiency and quality, rapid cell death in culture, and unknown response to cryopreservation prevent them from becoming a reliable and flexible in vitro cardiac model. Combing the use of a reversible inhibitor of myosin II ATPase, (-)-blebbistatin (Bleb), and multiple optimization steps of the isolation procedure, we achieved a 2.74-fold increase in cell viability over traditional methods, accompanied by better cellular morphology, minimally perturbed gene expression, intact electrophysiology, and normal neurohormonal signaling. Further optimization of culture conditions established a method that was capable of maintaining optimal cell viability, morphology, and mitochondrial respiration for at least 7 days. Most importantly, we successfully cryopreserved hPCMs, which were structurally, molecularly, and functionally intact after undergoing the freeze-thaw cycle. hPCMs demonstrated greater sensitivity towards a set of cardiotoxic drugs, compared to human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Further dissection of cardiomyocyte drug response at both the population and single-cell transcriptomic level revealed that hPCM responses were more pronouncedly enriched in cardiac function, whereas hiPSC-CMs responses reflected cardiac development. Together, we established a full set of methodologies for the efficient isolation and prolonged maintenance of functional primary adult human cardiomyocytes in vitro, unlocking their potential as a cellular model for cardiovascular research, drug discovery, and safety pharmacology.
Enhancing exposure therapy for posttraumatic stress disorder (PTSD): a randomized clinical trial of virtual reality and imaginal exposure with a cognitive enhancer
Authors: Difede JoAnn , Rothbaum Barbara O. , Rizzo Albert A. , Wyka Katarzyna , Spielman Lisa , Reist Christopher , Roy Michael J. , Jovanovic Tanja , Norrholm Seth D. , Cukor Judith , Olden Megan , Glatt Charles E. , Lee Francis S.
Published: July 2022

Posttraumatic stress disorder (PTSD) is a significant public health issue. Yet, there are limited treatment options and no data to suggest which treatment will work for whom. We tested the efficacy of virtual reality exposure (VRE) or prolonged imaginal exposure (PE), augmented with D-cycloserine (DCS) for combat-related PTSD. As an exploratory aim, we examined whether brain-derived neurotrophic factor (BDNF) and fatty acid amide hydrolase (FAAH) moderated treatment response. Military personnel with PTSD (n = 192) were recruited into a multisite double-blind randomized controlled trial to receive nine weeks of VRE or PE, with DCS or placebo. Primary outcome was the improvement in symptom severity. Randomization was stratified by comorbid depression (MDD) and site. Participants in both VRE and PE showed similar meaningful clinical improvement with no difference between the treatment groups. A significant interaction (p = 0.45) suggested VRE was more effective for depressed participants (CAPS difference M = 3.51 [95% CI 1.17–5.86],p = 0.004, ES = 0.14) while PE was more effective for nondepressed participants (M = −8.87 [95% CI −11.33 to −6.40],p < 0.001, ES = −0.44). The main effect of DCS vs. placebo was not significant. Augmentation by MDD interaction (p = 0.073) suggested that depressed participants improved more on placebo (M = −8.43 [95% CI −10.98 to −5.88],p < 0.001, ES = −0.42); DCS and placebo were equally effective for nondepressed participants. There was an apparent moderating effect of BDNF Val66Met polymorphism on DCS augmentation (ES = 0.67). Met66 allele carriers improved more on DCS (ES = −0.25). FAAH 385 A carriers improved more than non-carriers (ES = 0.33), particularly those with MDD (ES = 0.62). This study provides a step toward precision therapeutics for PTSD by demonstrating that comorbid MDD and genetic markers may help guide treatment selection.

ClinicalTrials.gov Identifier: NCT01352637.
A self-amplifying USP14-TAZ loop drives the progression and liver metastasis of pancreatic ductal adenocarcinoma
Authors: Zhao Chunle , Gong Jun , Bai Yu , Yin Taoyuan , Zhou Min , Pan Shutao , Liu Yuhui , Gao Yang , Zhang Zhenxiong , Shi Yongkang , Zhu Feng , Zhang Hang , Wang Min , Qin Renyi
Published: July 2022

With a 5-year survival rate of approximately 10%, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies in humans. A poor understanding of the underlying biology has resulted in a lack of effective targeted therapeutic strategies. Tissue microarray and bioinformatics analyses have revealed that the downstream transcriptional coactivator of the Hippo pathway, transcriptional coactivator with PDZ-binding motif (TAZ), might be a therapeutic target in PDAC. Since pharmacological inhibition of TAZ is challenging, we performed unbiased deubiquitinase (DUB) library screening to explore the pivotal regulators of TAZ ubiquitination as potential targets in PDAC models. We found that USP14 contributed to Yes-associated protein (YAP)/TAZ transcriptional activity and stabilized TAZ but not YAP. Mechanistically, USP14 catalyzed the K48-linked deubiquitination of TAZ to promote TAZ stabilization. Moreover, TAZ facilitated the transcription of USP14 by binding to the TEA domain transcription factor (TEAD) 1/4 response element in the promoter of USP14. USP14 was found to modulate the expression of TAZ downstream target genes through a feedback mechanism and ultimately promoted cancer progression and liver metastasis in PDAC models in vitro and in vivo. In addition, depletion of USP14 led to proteasome-dependent degradation of TAZ and ultimately arrested PDAC tumour growth and liver metastasis. A strong positive correlation between USP14 and TAZ expression was also detected in PDAC patients. The small molecule inhibitor of USP14 catalytic activity, IU1, inhibited the development of PDAC in subcutaneous xenograft and liver metastasis models. Overall, our data strongly suggested that the self-amplifying USP14-TAZ loop was a previously unrecognized mechanism causing upregulated TAZ expression, and identified USP14 as a viable therapeutic target in PDAC.
Hypoxia aggravates ferroptosis in RPE cells by promoting the Fenton reaction
Authors: Henning Yoshiyuki , Blind Ursula Sarah , Larafa Safa , Matschke Johann , Fandrey Joachim
Published: July 2022

Oxidative stress and hypoxia in the retinal pigment epithelium (RPE) have long been considered major risk factors in the pathophysiology of age-related macular degeneration (AMD), but systematic investigation of the interplay between these two risk factors was lacking. For this purpose, we treated a human RPE cell line (ARPE-19) with sodium iodate (SI), an oxidative stress agent, together with dimethyloxalylglycine (DMOG) which leads to stabilization of hypoxia-inducible factors (HIFs), key regulators of cellular adaptation to hypoxic conditions. We found that HIF stabilization aggravated oxidative stress-induced cell death by SI and iron-dependent ferroptosis was identified as the main cell death mechanism. Ferroptotic cell death depends on the Fenton reaction where H2O2 and iron react to generate hydroxyl radicals which trigger lipid peroxidation. Our findings clearly provide evidence for superoxide dismutase (SOD) driven H2O2 production fostering the Fenton reaction as indicated by triggered SOD activity upon DMOG + SI treatment as well as by reduced cell death levels upon SOD2 knockdown. In addition, iron transporters involved in non-transferrin-bound Fe2+ import as well as intracellular iron levels were also upregulated. Consequently, chelation of Fe2+ by 2’2-Bipyridyl completely rescued cells. Taken together, we show for the first time that HIF stabilization under oxidative stress conditions aggravates ferroptotic cell death in RPE cells. Thus, our study provides a novel link between hypoxia, oxidative stress and iron metabolism in AMD pathophysiology. Since iron accumulation and altered iron metabolism are characteristic features of AMD retinas and RPE cells, our cell culture model is suitable for high-throughput screening of new treatment approaches against AMD.
Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation
Authors: Grieco Giuseppina E. , Brusco Noemi , Fignani Daniela , Nigi Laura , Formichi Caterina , Licata Giada , Marselli Lorella , Marchetti Piero , Salvini Laura , Tinti Laura , Po Agnese , Ferretti Elisabetta , Sebastiani Guido , Dotta Francesco
Published: July 2022

The loss of functional β-cell mass in type 2 diabetes (T2D) is associated with molecular events that include β-cell apoptosis, dysfunction and/or dedifferentiation. MicroRNA miR-184-3p has been shown to be involved in several β-cell functions, including insulin secretion, proliferation and survival. However, the downstream targets and upstream regulators of miR-184-3p have not been fully elucidated. Here, we show reduced miR-184-3p levels in human T2D pancreatic islets, whereas its direct target CREB regulated transcription coactivator 1 (CRTC1) was increased and protects β-cells from lipotoxicity- and inflammation-induced apoptosis. Downregulation of miR-184-3p in β-cells leads to upregulation of CRTC1 at both the mRNA and protein levels. Remarkably, the protective effect of miR-184-3p is dependent on CRTC1, as its silencing in human β-cells abrogates the protective mechanism mediated by inhibition of miR-184-3p. Furthermore, in accordance with miR-184-3p downregulation, we also found that the β-cell-specific transcription factor NKX6.1, DNA-binding sites of which are predicted in the promoter sequence of human and mouse MIR184 gene, is reduced in human pancreatic T2D islets. Using chromatin immunoprecipitation analysis and mRNA silencing experiments, we demonstrated that NKX6.1 directly controls both human and murine miR-184 expression. In summary, we provide evidence that the decrease in NKX6.1 expression is accompanied by a significant reduction in miR-184-3p expression and that reduction of miR-184-3p protects β-cells from apoptosis through a CRTC1-dependent mechanism.
Facet nanoarchitectonics of visible-light driven Ag3PO4 photocatalytic micromotors: Tuning motion for biofilm eradication
Authors: Rojas Daniel , Kuthanova Michaela , Dolezelikova Kristyna , Pumera Martin
Published: July 2022

The customized design of micro-/nanomotors represents one of the main research topics in the field of micro-/nanomotors; however, the effects of different crystal facets on micromotor movement are often neglected. In this work, self-propelled amorphous, cubic, and tetrahedral Ag3PO4 particles were synthetized using a scalable precipitation method. Their programmable morphologies exhibited different motion properties under fuel-free and surfactant-free conditions and visible light irradiation. Differences in these motion properties were observed according to morphology and correlated with photocatalytic activity. Moreover, Ag3PO4 micromotors are inherently fluorescent, which allows fluorescence-based tracking. Furthermore, bacterial biofilms represent a major concern in modern society since most of them are antibiotic resistant. The as-prepared self-propelled particles exhibited morphologically dependent antibiofilm activities toward gram-positive and gram-negative bacteria. The enhanced diffusion of the particles promoted biofilm removal in comparison with static control experiments, realizing the possibility of a new class of light-driven biofilm-eradicating micromotors that do not require the use of both H2O2 and UV light.
Genome-wide association study identifies Sjögren’s risk loci with functional implications in immune and glandular cells
Authors: Khatri Bhuwan , Tessneer Kandice L. , Rasmussen Astrid , Aghakhanian Farhang , Reksten Tove Ragna , Adler Adam , Alevizos Ilias , Anaya Juan-Manuel , Aqrawi Lara A. , Baecklund Eva , Brun Johan G. , Bucher Sara Magnusson , Eloranta Maija-Leena , Engelke Fiona , Forsblad-d’Elia Helena , Glenn Stuart B. , Hammenfors Daniel , Imgenberg-Kreuz Juliana , Jensen Janicke Liaaen , Johnsen Svein Joar Auglænd , Jonsson Malin V. , Kvarnström Marika , Kelly Jennifer A. , Li He , Mandl Thomas , Martín Javier , Nocturne Gaétane , Norheim Katrine Brække , Palm Øyvind , Skarstein Kathrine , Stolarczyk Anna M. , Taylor Kimberly E. , Teruel Maria , Theander Elke , Venuturupalli Swamy , Wallace Daniel J. , Grundahl Kiely M. , Hefner Kimberly S. , Radfar Lida , Lewis David M. , Stone Donald U. , Kaufman C. Erick , Brennan Michael T. , Guthridge Joel M. , James Judith A. , Scofield R. Hal , Gaffney Patrick M. , Criswell Lindsey A. , Jonsson Roland , Eriksson Per , Bowman Simon J. , Omdal Roald , Rönnblom Lars , Warner Blake , Rischmueller Maureen , Witte Torsten , Farris A. Darise , Mariette Xavier , Alarcon-Riquelme Marta E. ,   PRECISESADS Clinical Consortium, Shiboski Caroline H. ,   Sjögren’s International Collaborative Clinical Alliance (SICCA), Wahren-Herlenius Marie , Ng Wan-Fai ,   UK Primary Sjögren’s Syndrome Registry, Sivils Kathy L. , Adrianto Indra , Nordmark Gunnel , Lessard Christopher J.
Published: July 2022

Sjögren’s disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren’s cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands.
Dietary protein increases T-cell-independent sIgA production through changes in gut microbiota-derived extracellular vesicles
Authors: Tan Jian , Ni Duan , Taitz Jemma , Pinget Gabriela Veronica , Read Mark , Senior Alistair , Wali Jibran Abdul , Elnour Reem , Shanahan Erin , Wu Huiling , Chadban Steven J. , Nanan Ralph , King Nicholas Jonathan Cole , Grau Georges Emile , Simpson Stephen J. , Macia Laurence
Published: July 2022

Secretory IgA is a key mucosal component ensuring host-microbiota mutualism. Here we use nutritional geometry modelling in mice fed 10 different macronutrient-defined, isocaloric diets, and identify dietary protein as the major driver of secretory IgA production. Protein-driven secretory IgA induction is not mediated by T-cell-dependent pathways or changes in gut microbiota composition. Instead, the microbiota of high protein fed mice produces significantly higher quantities of extracellular vesicles, compared to those of mice fed high-carbohydrate or high-fat diets. These extracellular vesicles activate Toll-like receptor 4 to increase the epithelial expression of IgA-inducing cytokine, APRIL, B cell chemokine, CCL28, and the IgA transporter, PIGR. We show that succinate, produced in high concentrations by microbiota of high protein fed animals, increases generation of reactive oxygen species by bacteria, which in turn promotes extracellular vesicles production. Here we establish a link between dietary macronutrient composition, gut microbial extracellular vesicles release and host secretory IgA response.
Large-area transfer of two-dimensional materials free of cracks, contamination and wrinkles via controllable conformal contact
Authors: Zhao Yixuan , Song Yuqing , Hu Zhaoning , Wang Wendong , Chang Zhenghua , Zhang Yan , Lu Qi , Wu Haotian , Liao Junhao , Zou Wentao , Gao Xin , Jia Kaicheng , Zhuo La , Hu Jingyi , Xie Qin , Zhang Rui , Wang Xiaorui , Sun Luzhao , Li Fangfang , Zheng Liming , Wang Ming , Yang Jiawei , Mao Boyang , Fang Tiantian , Wang Fuyi , Zhong Haotian , Liu Wenlin , Yan Rui , Yin Jianbo , Zhang Yanfeng , Wei Yujie , Peng Hailin , Lin Li , Liu Zhongfan
Published: July 2022

The availability of graphene and other two-dimensional (2D) materials on a wide range of substrates forms the basis for large-area applications, such as graphene integration with silicon-based technologies, which requires graphene on silicon with outperforming carrier mobilities. However, 2D materials were only produced on limited archetypal substrates by chemical vapor deposition approaches. Reliable after-growth transfer techniques, that do not produce cracks, contamination, and wrinkles, are critical for layering 2D materials onto arbitrary substrates. Here we show that, by incorporating oxhydryl groups-containing volatile molecules, the supporting films can be deformed under heat to achieve a controllable conformal contact, enabling the large-area transfer of 2D films without cracks, contamination, and wrinkles. The resulting conformity with enhanced adhesion facilitates the direct delamination of supporting films from graphene, providing ultraclean surfaces and carrier mobilities up to 1,420,000 cm2 V−1 s−1 at 4 K.
Divergent synthesis of benzazepines and bridged polycycloalkanones via dearomative rearrangement
Authors: Shi Qiu , Liao Zhehui , Liu Zhili , Wen Jiajia , Li Chenguang , He Jiamin , Deng Jiazhen , Cen Shan , Cao Tongxiang , Zhou Jinming , Zhu Shifa
Published: July 2022

The dearomative functionalization of aromatic compounds represents a fascinating but challenging transformation, as it typically needs to overcome a great kinetic barrier. Here, a catalyst-free dearomative rearrangement of o-nitrophenyl alkyne is successfully established by leveraging the remote oxygen transposition and a weak N-O bond acceleration. This reaction features high atom-, step- and redox-economy, which provides a divergent entry to a series of biologically important benzazepines and bridged polycycloalkanones. The reaction is proposed to proceed through a tandem oxygen transfer cyclization/(3 + 2) cycloaddition/(homo-)hetero-Claisen rearrangement reaction. The resulting polycyclic system is richly decorated with transformable functionalities, such as carbonyl, imine and diene, which enables diversity-oriented synthesis of alkaloid-like polycyclic framework.
Cross-validation of distance measurements in proteins by PELDOR/DEER and single-molecule FRET
Authors: Peter Martin F. , Gebhardt Christian , Mächtel Rebecca , Muñoz Gabriel G. Moya , Glaenzer Janin , Narducci Alessandra , Thomas Gavin H. , Cordes Thorben , Hagelueken Gregor
Published: July 2022

Pulsed electron-electron double resonance spectroscopy (PELDOR/DEER) and single-molecule Förster resonance energy transfer spectroscopy (smFRET) are frequently used to determine conformational changes, structural heterogeneity, and inter probe distances in biological macromolecules. They provide qualitative information that facilitates mechanistic understanding of biochemical processes and quantitative data for structural modelling. To provide a comprehensive comparison of the accuracy of PELDOR/DEER and smFRET, we use a library of double cysteine variants of four proteins that undergo large-scale conformational changes upon ligand binding. With either method, we use established standard experimental protocols and data analysis routines to determine inter-probe distances in the presence and absence of ligands. The results are compared to distance predictions from structural models. Despite an overall satisfying and similar distance accuracy, some inconsistencies are identified, which we attribute to the use of cryoprotectants for PELDOR/DEER and label-protein interactions for smFRET. This large-scale cross-validation of PELDOR/DEER and smFRET highlights the strengths, weaknesses, and synergies of these two important and complementary tools in integrative structural biology.
Defunctionalizing intracellular organelles such as mitochondria and peroxisomes with engineered phospholipase A/acyltransferases
Authors: Watanabe Satoshi , Nihongaki Yuta , Itoh Kie , Uyama Toru , Toda Satoshi , Watanabe Shigeki , Inoue Takanari
Published: July 2022

Organelles vitally achieve multifaceted functions to maintain cellular homeostasis. Genetic and pharmacological approaches to manipulate individual organelles are powerful in probing their physiological roles. However, many of them are either slow in action, limited to certain organelles, or rely on toxic agents. Here, we design a generalizable molecular tool utilizing phospholipase A/acyltransferases (PLAATs) for rapid defunctionalization of organelles via remodeling of the membrane phospholipids. In particular, we identify catalytically active PLAAT truncates with minimal unfavorable characteristics. Chemically-induced translocation of the optimized PLAAT to the mitochondria surface results in their rapid deformation in a phospholipase activity dependent manner, followed by loss of luminal proteins as well as dissipated membrane potential, thus invalidating the functionality. To demonstrate wide applicability, we then adapt the molecular tool in peroxisomes, and observe leakage of matrix-resident functional proteins. The technique is compatible with optogenetic control, viral delivery and operation in primary neuronal cultures. Due to such versatility, the PLAAT strategy should prove useful in studying organelle biology of diverse contexts.
Transcription factor network analysis identifies REST/NRSF as an intrinsic regulator of CNS regeneration in mice
Authors: Cheng Yuyan , Yin Yuqin , Zhang Alice , Bernstein Alexander M. , Kawaguchi Riki , Gao Kun , Potter Kyra , Gilbert Hui-Ya , Ao Yan , Ou Jing , Fricano-Kugler Catherine J. , Goldberg Jeffrey L. , He Zhigang , Woolf Clifford J. , Sofroniew Michael V. , Benowitz Larry I. , Geschwind Daniel H.
Published: July 2022

The inability of neurons to regenerate long axons within the CNS is a major impediment to improving outcome after spinal cord injury, stroke, and other CNS insults. Recent advances have uncovered an intrinsic program that involves coordinate regulation by multiple transcription factors that can be manipulated to enhance growth in the peripheral nervous system. Here, we use a systems genomics approach to characterize regulatory relationships of regeneration-associated transcription factors, identifying RE1-Silencing Transcription Factor (REST; Neuron-Restrictive Silencer Factor, NRSF) as a predicted upstream suppressor of a pro-regenerative gene program associated with axon regeneration in the CNS. We validate our predictions using multiple paradigms, showing that mature mice bearing cell type-specific deletions of REST or expressing dominant-negative mutant REST show improved regeneration of the corticospinal tract and optic nerve after spinal cord injury and optic nerve crush, which is accompanied by upregulation of regeneration-associated genes in cortical motor neurons and retinal ganglion cells, respectively. These analyses identify a role for REST as an upstream suppressor of the intrinsic regenerative program in the CNS and demonstrate the utility of a systems biology approach involving integrative genomics and bio-informatics to prioritize hypotheses relevant to CNS repair.
SARS-CoV-2 VOC type and biological sex affect molnupiravir efficacy in severe COVID-19 dwarf hamster model
Authors: Lieber Carolin M. , Cox Robert M. , Sourimant Julien , Wolf Josef D. , Juergens Kate , Phung Quynh , Saindane Manohar T. , Smith Meghan K. , Sticher Zachary M. , Kalykhalov Alexander A. , Natchus Michael G. , Painter George R. , Sakamoto Kaori , Greninger Alexander L. , Plemper Richard K.
Published: July 2022

SARS-CoV-2 variants of concern (VOC) have triggered infection waves. Oral antivirals such as molnupiravir promise to improve disease management, but efficacy against VOC delta was questioned and potency against omicron is unknown. This study evaluates molnupiravir against VOC in human airway epithelium organoids, ferrets, and a lethal Roborovski dwarf hamster model of severe COVID-19-like lung injury. VOC were equally inhibited by molnupiravir in cells and organoids. Treatment reduced shedding in ferrets and prevented transmission. Pathogenicity in dwarf hamsters was VOC-dependent and highest for delta, gamma, and omicron. All molnupiravir-treated dwarf hamsters survived, showing reduction in lung virus load from one (delta) to four (gamma) orders of magnitude. Treatment effect size varied in individual dwarf hamsters infected with omicron and was significant in males, but not females. The dwarf hamster model recapitulates mixed efficacy of molnupiravir in human trials and alerts that benefit must be reassessed in vivo as VOC evolve.
Three-dimensional printing of photonic colloidal glasses into objects with isotropic structural color
Authors: Demirörs Ahmet F. , Poloni Erik , Chiesa Maddalena , Bargardi Fabio L. , Binelli Marco R. , Woigk Wilhelm , de Castro Lucas D. C. , Kleger Nicole , Coulter Fergal B. , Sicher Alba , Galinski Henning , Scheffold Frank , Studart André R.
Published: July 2022

Structural color is frequently exploited by living organisms for biological functions and has also been translated into synthetic materials as a more durable and less hazardous alternative to conventional pigments. Additive manufacturing approaches were recently exploited for the fabrication of exquisite photonic objects, but the angle-dependence observed limits a broader application of structural color in synthetic systems. Here, we propose a manufacturing platform for the 3D printing of complex-shaped objects that display isotropic structural color generated from photonic colloidal glasses. Structurally colored objects are printed from aqueous colloidal inks containing monodisperse silica particles, carbon black, and a gel-forming copolymer. Rheology and Small-Angle-X-Ray-Scattering measurements are performed to identify the processing conditions leading to printed objects with tunable structural colors. Multimaterial printing is eventually used to create complex-shaped objects with multiple structural colors using silica and carbon as abundant and sustainable building blocks.
Thermal control of the topological edge flow in nonlinear photonic lattices
Authors: Jung Pawel S. , Pyrialakos Georgios G. , Wu Fan O. , Parto Midya , Khajavikhan Mercedeh , Krolikowski Wieslaw , Christodoulides Demetrios N.
Published: July 2022

The chaotic evolution resulting from the interplay between topology and nonlinearity in photonic systems generally forbids the sustainability of optical currents. Here, we systematically explore the nonlinear evolution dynamics in topological photonic lattices within the framework of optical thermodynamics. By considering an archetypical two-dimensional Haldane photonic lattice, we discover several prethermal states beyond the topological phase transition point and a stable global equilibrium response, associated with a specific optical temperature and chemical potential. Along these lines, we provide a consistent thermodynamic methodology for both controlling and maximizing the unidirectional power flow in the topological edge states. This can be achieved by either employing cross-phase interactions between two subsystems or by exploiting self-heating effects in disordered or Floquet topological lattices. Our results indicate that photonic topological systems can in fact support robust photon transport processes even under the extreme complexity introduced by nonlinearity, an important feature for contemporary topological applications in photonics.
Real-time precision opto-control of chemical processes in live cells
Authors: Clark Matthew G. , Gonzalez Gil A. , Luo Yiyang , Aldana-Mendoza Jesus A. , Carlsen Mark S. , Eakins Gregory , Dai Mingji , Zhang Chi
Published: July 2022

Precision control of molecular activities and chemical reactions in live cells is a long-sought capability by life scientists. No existing technology can probe molecular targets in cells and simultaneously control the activities of only these targets at high spatial precision. We develop a real-time precision opto-control (RPOC) technology that detects a chemical-specific optical response from molecular targets during laser scanning and uses the optical signal to couple a separate laser to only interact with these molecules without affecting other sample locations. We demonstrate precision control of molecular states of a photochromic molecule in different regions of the cells. We also synthesize a photoswitchable compound and use it with RPOC to achieve site-specific inhibition of microtubule polymerization and control of organelle dynamics in live cells. RPOC can automatically detect and control biomolecular activities and chemical processes in dynamic living samples with submicron spatial accuracy, fast response time, and high chemical specificity.
Gata6+ resident peritoneal macrophages promote the growth of liver metastasis
Authors: Hossain Mokarram , Shim Raymond , Lee Woo-Yong , Sharpe Arlene H. , Kubes Paul
Published: July 2022

Emerging evidence suggests that resident macrophages within tissues are enablers of tumor growth. However, a second population of resident macrophages surrounds all visceral organs within the cavities and nothing is known about these GATA6+ large peritoneal macrophages (GLPMs) despite their ability to invade injured visceral organs by sensing danger signals. Here, we show that GLPMs invade growing metastases that breach the visceral mesothelium of the liver via the “find me signal”, ATP. Depleting GLPMs either by pharmacological or genetic tools, reduces metastases growth. Apoptotic bodies from tumor cells induces programmed cell death ligand 1 (PD-L1) upregulation on GLPMs which block CD8+ T cell function. Direct targeting of GLPMs by intraperitoneal but not intravenous administration of anti-PD-L1 reduces tumor growth. Thermal ablation of liver metastases recruits huge numbers of GLPMs and enables rapid regrowth of tumors. GLPMs contribute to metastatic growth and tumor recurrence.
CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors
Authors: Lloyd Sarah M. , Leon Daniel B. , Brady Mari O. , Rodriguez Deborah , McReynolds Madison P. , Kweon Junghun , Neely Amy E. , Blumensaadt Laura A. , Ho Patric J. , Bao Xiaomin
Published: July 2022

Progenitors in epithelial tissues, such as human skin epidermis, continuously make fate decisions between self-renewal and differentiation. Here we show that the Super Elongation Complex (SEC) controls progenitor fate decisions by directly suppressing a group of “rapid response” genes, which feature high enrichment of paused Pol II in the progenitor state and robust Pol II elongation in differentiation. SEC’s repressive role is dependent on the AFF1 scaffold, but not AFF4. In the progenitor state, AFF1-SEC associates with the HEXIM1-containing inactive CDK9 to suppress these rapid-response genes. A key rapid-response SEC target is ATF3, which promotes the upregulation of differentiation-activating transcription factors (GRHL3, OVOL1, PRDM1, ZNF750) to advance terminal differentiation. SEC peptidomimetic inhibitors or PKC signaling activates CDK9 and rapidly induces these transcription factors within hours in keratinocytes. Thus, our data suggest that the activity switch of SEC-associated CDK9 underlies the initial processes bifurcating progenitor fates between self-renewal and differentiation.
Pathogen-selective killing by guanylate-binding proteins as a molecular mechanism leading to inflammasome signaling
Authors: Feng Shouya , Enosi Tuipulotu Daniel , Pandey Abhimanu , Jing Weidong , Shen Cheng , Ngo Chinh , Tessema Melkamu B. , Li Fei-Ju , Fox Daniel , Mathur Anukriti , Zhao Anyang , Wang Runli , Pfeffer Klaus , Degrandi Daniel , Yamamoto Masahiro , Reading Patrick C. , Burgio Gaetan , Man Si Ming
Published: July 2022

Inflammasomes are cytosolic signaling complexes capable of sensing microbial ligands to trigger inflammation and cell death responses. Here, we show that guanylate-binding proteins (GBPs) mediate pathogen-selective inflammasome activation. We show that mouse GBP1 and GBP3 are specifically required for inflammasome activation during infection with the cytosolic bacterium Francisella novicida. We show that the selectivity of mouse GBP1 and GBP3 derives from a region within the N-terminal domain containing charged and hydrophobic amino acids, which binds to and facilitates direct killing of F. novicida and Neisseria meningitidis, but not other bacteria or mammalian cells. This pathogen-selective recognition by this region of mouse GBP1 and GBP3 leads to pathogen membrane rupture and release of intracellular content for inflammasome sensing. Our results imply that GBPs discriminate between pathogens, confer activation of innate immunity, and provide a host-inspired roadmap for the design of synthetic antimicrobial peptides that may be of use against emerging and re-emerging pathogens.
Pyro-catalysis for tooth whitening via oral temperature fluctuation
Authors: Wang Yang , Wang Shuhao , Meng Yanze , Liu Zhen , Li Dijie , Bai Yunyang , Yuan Guoliang , Wang Yaojin , Zhang Xuehui , Li Xiaoguang , Deng Xuliang
Published: July 2022

Tooth whitening has recently become one of the most popular aesthetic dentistry procedures. Beyond classic hydrogen peroxide-based whitening agents, photo-catalysts and piezo-catalysts have been demonstrated for non-destructive on-demand tooth whitening. However, their usage has been challenged due to the relatively limited physical stimuli of light irradiation and ultrasonic mechanical vibration. To address this challenge, we report here a non-destructive and convenient tooth whitening strategy based on the pyro-catalysis effect, realized via ubiquitous oral motion-induced temperature fluctuations. Degradation of organic dyes via pyro-catalysis is performed under cooling/heating cycling to simulate natural temperature fluctuations associated with intake and speech. Teeth stained by habitual beverages and flavorings can be whitened by the pyroelectric particles-embedded hydrogel under a small surrounding temperature fluctuation. Furthermore, the pyro-catalysis-based tooth whitening procedure exhibits a therapeutic biosafety and sustainability. In view of the exemplary demonstration, the most prevalent oral temperature fluctuation will enable the pyro-catalysis-based tooth whitening strategy to have tremendous potential for practical applications.
Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade
Authors: Kaur Gurman , Porter Caroline B. M. , Ashenberg Orr , Lee Jack , Riesenfeld Samantha J. , Hofree Matan , Aggelakopoulou Maria , Subramanian Ayshwarya , Kuttikkatte Subita Balaram , Attfield Kathrine E. , Desel Christiane A. E. , Davies Jessica L. , Evans Hayley G. , Avraham-Davidi Inbal , Nguyen Lan T. , Dionne Danielle A. , Neumann Anna E. , Jensen Lise Torp , Barber Thomas R. , Soilleux Elizabeth , Carrington Mary , McVean Gil , Rozenblatt-Rosen Orit , Regev Aviv , Fugger Lars
Published: July 2022

Fetal growth restriction (FGR) affects 5–10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicateKIRandHLAgenes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment.
Orbitofrontal cortex contributes to the comparison of values underlying economic choices
Authors: Ballesta Sébastien , Shi Weikang , Padoa-Schioppa Camillo
Published: July 2022

Economic choices between goods entail the computation and comparison of subjective values. Previous studies examined neuronal activity in the orbitofrontal cortex (OFC) of monkeys choosing between different types of juices. Three groups of neurons were identified: offer value cells encoding the value of individual offers, chosen juice cells encoding the identity of the chosen juice, and chosen value cells encoding the value of the chosen offer. The encoded variables capture both the input (offer value) and the output (chosen juice, chosen value) of the decision process, suggesting that values are compared within OFC. Recent work demonstrates that choices are causally linked to the activity of offer value cells. Conversely, the hypothesis that OFC contributes to value comparison has not been confirmed. Here we show that weak electrical stimulation of OFC specifically disrupts value comparison without altering offer values. This result implies that neuronal populations in OFC participate in value comparison.
Age-dependent effects of blue light exposure on lifespan, neurodegeneration, and mitochondria physiology in Drosophila melanogaster
Authors: Song Yujuan , Yang Jun , Law Alexander D. , Hendrix David A. , Kretzschmar Doris , Robinson Matthew , Giebultowicz Jadwiga M.
Published: July 2022

Blue light is a predominant component of light emitting devices (LEDs), which are increasingly present in our environment. There is already accumulating evidence that blue light exposure causes damage to retinal cells in vitro and in vivo; however, much less is known about potential effects of blue light on non-retinal cells. That blue light may be detrimental at the organismal level independent from retinal effect was recently shown by findings that it reduces lifespan in worms and also in flies with genetically ablated retinas. Here, we investigated the effects of blue light exposure across the fly lifespan and found that susceptibility to blue light stress is strongly age-dependent. The blue light of the same intensity and duration reduced survival and increased neurodegeneration more significantly in old flies than in young flies. These differences appear to be caused, at least in part, by impairments of mitochondrial respiratory function. We report that blue light significantly reduces the activity of Complex II in the electron transport system and decrease the biochemical activity of succinate dehydrogenase in both young and old flies. In addition, complex I and complex IV activities are reduced by age, as are ATP levels. We therefore propose that older flies are more sensitive to blue light because the light-induced mitochondrial damage potentiates the age-related impairments in energy metabolism that occurs even in darkness. Taken together, our results show that damaging effects of blue light at the organismal level are strongly age dependent and are associated with reduced activity of specific components of energy producing pathways in mitochondria.