bluuebunny/crossref_metadata_2025 huggingface dataset:
Biological Innovation without Intellectual Property Rights: Cottonseed Markets in the Antebellum American South
Authors: Rhode Paul W.
Published: January 2021

The Antebellum American South experienced rapid biological innovation centered around an active market for new cotton seed varieties, despite the absence of intellectual property rights. Contemporaries complained new seed was initially offered at high prices, which subsequently collapsed. Using local newspaper evidence, this paper documents this market’s operation. It then rationalizes the price movements given the potential of improved seed to multiply at finite rates. The initial prices were sufficiently high to provide meaningful incentives to innovate. This study also identifies information problems affecting the cotton seed market, leading observers to claim too many new varieties were released, not too few.
Differences in perceptions of transition readiness between parents and teens with congenital heart disease: do parents and teens agree?
Authors: Harrison David , Gurvitz Michelle , Yu Sunkyung , Lowery Ray E. , Afton Katherine , Yetman Angela , Cramer Jonathan , Rudd Nancy , Cohen Scott , Gongwer Russell , Uzark Karen
Published: January 2021

Background:

Amongst patients with CHD, the time of transition to adulthood is associated with lapses in care leading to significant morbidity. The purpose of this study was to identify differences in perceptions between parents and teens in regard to transition readiness.

Methods:

Responses were collected from 175 teen–parent pairs via the validated CHD Transition Readiness survey and an information request checklist. The survey was distributed via an electronic tablet at a routine clinic visit.

Results:

Parents reported a perceived knowledge gap of 29.2% (the percentage of survey items in which a parent believes their teen does not know), compared to teens self-reporting an average of 25.9% of survey items in which they feel deficient (p = 0.01). Agreement was lowest for long-term medical needs, physical activities allowed, insurance, and education. In regard to self-management behaviours, agreement between parent and teen was slight to moderate (weighted κ statistic = 0.18 to 0.51). For self-efficacy, agreement ranged from slight to fair (weighted κ = 0.16 to 0.28). Teens were more likely to request information than their parents (79% versus 65% requesting at least one item) particularly in regard to pregnancy/contraception and insurance.

Conclusion:

Parents and teens differ in several key perceptions regarding knowledge, behaviours, and feelings related to the management of heart disease. Specifically, parents perceive a higher knowledge deficit, teens perceive higher self-efficacy, and parents and teens agree that self-management is low.
A case of a large type IV aortico–left ventricular tunnel successfully repaired at 1 day after birth
Authors: Ito Takahiro , Aoki Mitsuru , Hagino Ikuo , Umezu Kentaro
Published: January 2021

A rare case of a patient with a large type IV aortico–left ventricular tunnel who underwent successful repair at 1 day after birth was described. To the best of our knowledge, no such cases that aortic opening was over 10 mm have been reported in the English literature. Our case demonstrated no leak or significant aortic regurgitation by a two-patch repair.
Die Bedeutung fötaler und neonataler Motorik für die kindliche Entwicklung und die Früherkennung von Entwicklungsstörungen
Authors: Einspieler Christa , Zhang Dajie , Marschik Peter B.
Published: January 2021

Zusammenfassung. Theoretischer Hintergrund: Die von Central Pattern Generators (CPGs) generierten Bewegungen des Neugeborenen und jungen Säuglings haben eine lange pränatale Vorgeschichte. Fragestellung: Welche Bedeutung hat die Analyse der CPG-Aktivität, besonders der General Movements (GMs) in der entwicklungsneurologischen Diagnostik? Methode: Unsere Übersichtsarbeit bezieht sich auf Prechtl’s General Movement Assessment (GMA), das ab dem Frühgeborenenalter bis zum Ende des 5. Monats nach einer Termingeburt anwendbar ist. Ergebnisse: Das GMA ermöglicht die Vorhersage einer Zerebralparese mit einer Sensitivität von 98 % und einer Spezifität von 91 %. Abnormale cramped-synchronized GMs sind ein früher Marker für spastische Zerebralparesen. Das Fehlen von Fidgety Movements (im 3.–5. Monat) weist auf alle Formen der Zerebralparese hin und kann auch bei bestimmten genetischen Erkrankungen auftreten. Zwei von drei Säuglingen mit einer späteren Diagnose Autismus haben atypische GMs und fallen vor allem durch ihre Monotonie in den Bewegungen auf. Diskussion und Schlussfolgerung: Mittels GMA lassen sich mit großer Treffsicherheit typische Entwicklungsverläufe vorhersagen oder aber ein Risiko für einen atypischen Verlauf erkennen und somit frühzeitige Interventionen einleiten.
Frühe Prädiktoren der Sprachentwicklung von Kindern mit permanenter Hörstörung
Authors: Holzinger Daniel , Hofer Johannes , Dall Magdalena
Published: January 2021

Zusammenfassung. Theoretischer Hintergrund: Sprachentwicklungsverläufe bei Kindern mit Hörstörungen zeigen eine hohe und überwiegend ungeklärte Varianz. Fragestellung und Methode: Unsere Übersichtsarbeit präsentiert aktuelle Evidenz zu frühen Prädiktoren der Sprachentwicklung. Ergebnisse und Diskussion: Trotz deutlicher positiver Trends erreicht nur jedes zweite Kind ein Sprachentwicklungsniveau im Normbereich. Der Literaturüberblick ergibt signifikante kindbezogene und familiäre Prädiktoren mit eher geringer Beeinflussbarkeit. Als hoch prädiktiv für sprachliche Ergebnisse und zudem der Intervention zugänglich erweisen sich die frühe Erkennung und technische Versorgung mit Hörgeräten oder -implantaten und Aufnahme in die Frühförderung, konsistente Hörtechnikverwendung und/oder früher Zugang zur Gebärdensprache. Zudem zeigt sich die Qualität der täglichen Eltern-Kind-Interaktion als hocheffektiv für die Sprachentwicklung. Schlussfolgerung: Es bestätigt sich die Wirksamkeit aktueller Best Practice früher Erkennung, Versorgung und familienzentrierter Frühförderung.
Therapieprozesse in der Kinder- und Jugendlichenpsychotherapie
Authors: In-Albon Tina , Munsch Simone , Vonderlin Eva , Kalmar Julia , Brodard Fabrice , Flückiger Christoph , Gutzweiler Raphael , Kircher Andrea , Mander Johannes
Published: January 2021

Zusammenfassung. Theoretischer Hintergrund: Die Psychotherapieforschung zu therapeutischen Wirkfaktoren bei Kindern steckt in den Kinderschuhen. Mit dem Stundenbogen für Kinder und Jugendliche Patientenversion (SBKJ-P) wurde ein entsprechendes Messinstrument entwickelt. Die erfassten Wirkfaktoren sind Problemaktualisierung, Ressourcenaktivierung, Problembewältigung, motivationale Klärung als auch Rolle der Eltern und therapeutische Allianz. Fragestellung: Untersucht werden die Faktorstruktur, interne Konsistenz und konvergente Validität. Methode: Die Stichprobe umfasst 123 Kinder und Jugendliche (62 Mädchen) im Alter zwischen 7 und 18 Jahren ( MW = 13.1, SD = 3.03). Ergebnisse: Die Ergebnisse zeigen, dass der SBKJ-P ein verständliches, reliables und valides Instrument für die Prozess- und Verlaufsmessung von allgemeinen therapeutischen Wirkfaktoren darstellt. Diskussion und Schlussfolgerung: Der SBKJ-P erlaubt eine zuverlässige Einschätzung der Qualitätssicherung im psychotherapeutischen Prozess.
Fungal sporocarps house diverse and host-specific communities of fungicolous fungi
Authors: Maurice Sundy , Arnault Gontran , Nordén Jenni , Botnen Synnøve Smebye , Miettinen Otto , Kauserud Håvard
Published: January 2021

Sporocarps (fruit bodies) are the sexual reproductive stage in the life cycle of many fungi. They are highly nutritious and consequently vulnerable to grazing by birds and small mammals, and invertebrates, and can be infected by microbial and fungal parasites and pathogens. The complexity of communities thriving inside sporocarps is largely unknown. In this study, we revealed the diversity, taxonomic composition and host preference of fungicolous fungi (i.e., fungi that feed on other fungi) in sporocarps. We carried out DNA metabarcoding of the ITS2 region from 176 sporocarps of 11 wood-decay fungal host species, all collected within a forest in northeast Finland. We assessed the influence of sporocarp traits, such as lifespan, morphology and size, on the fungicolous fungal community. The level of colonisation by fungicolous fungi, measured as the proportion of non-host ITS2 reads, varied between 2.8–39.8% across the 11 host species and was largely dominated by Ascomycota. Host species was the major determinant of the community composition and diversity of fungicolous fungi, suggesting that host adaptation is important for many fungicolous fungi. Furthermore, the alpha diversity was consistently higher in short-lived and resupinate sporocarps compared to long-lived and pileate ones, perhaps due to a more hostile environment for fungal growth in the latter too. The fungicolous fungi represented numerous lineages in the fungal tree of life, among which a significant portion was poorly represented with reference sequences in databases.
Hard for humans, hard for machines: predicting readmission after psychiatric hospitalization using narrative notes
Authors: Boag William , Kovaleva Olga , McCoy Thomas H. , Rumshisky Anna , Szolovits Peter , Perlis Roy H.
Published: January 2021

Machine learning has been suggested as a means of identifying individuals at greatest risk for hospital readmission, including psychiatric readmission. We sought to compare the performance of predictive models that use interpretable representations derived via topic modeling to the performance of human experts and nonexperts. We examined all 5076 admissions to a general psychiatry inpatient unit between 2009 and 2016 using electronic health records. We developed multiple models to predict 180-day readmission for these admissions based on features derived from narrative discharge summaries, augmented by baseline sociodemographic and clinical features. We developed models using a training set comprising 70% of the cohort and evaluated on the remaining 30%. Baseline models using demographic features for prediction achieved an area under the curve (AUC) of 0.675 [95% CI 0.674–0.676] on an independent testing set, while language-based models also incorporating bag-of-words features, discharge summaries topics identified by Latent Dirichlet allocation (LDA), and prior psychiatric admissions achieved AUC of 0.726 [95% CI 0.725–0.727]. To characterize the difficulty of the task, we also compared the performance of these classifiers to both expert and nonexpert human raters, with and without feedback, on a subset of 75 test cases. These models outperformed humans on average, including predictions by experienced psychiatrists. Typical note tokens or topics associated with readmission risk were related to pregnancy/postpartum state, family relationships, and psychosis.
Anomaly detection to predict relapse risk in schizophrenia
Authors: Henson Philip , D’Mello Ryan , Vaidyam Aditya , Keshavan Matcheri , Torous John
Published: January 2021

The integration of technology in clinical care is growing rapidly and has become especially relevant during the global COVID-19 pandemic. Smartphone-based digital phenotyping, or the use of integrated sensors to identify patterns in behavior and symptomatology, has shown potential in detecting subtle moment-to-moment changes. These changes, often referred to as anomalies, represent significant deviations from an individual’s baseline, may be useful in informing the risk of relapse in serious mental illness. Our investigation of smartphone-based anomaly detection resulted in 89% sensitivity and 75% specificity for predicting relapse in schizophrenia. These results demonstrate the potential of longitudinal collection of real-time behavior and symptomatology via smartphones and the clinical utility of individualized analysis. Future studies are necessary to explore how specificity can be improved, just-in-time adaptive interventions utilized, and clinical integration achieved.
Reducing intrusive memories after trauma via a brief cognitive task intervention in the hospital emergency department: an exploratory pilot randomised controlled trial
Authors: Kanstrup Marie , Singh Laura , Göransson Katarina E. , Widoff Julia , Taylor Rod S. , Gamble Beau , Iyadurai Lalitha , Moulds Michelle L. , Holmes Emily A.
Published: January 2021

Intrusive memories are common after trauma, and can cause significant distress. Interventions to prevent/reduce the occurrence of this core clinical feature of posttraumatic stress disorder are needed; they should be easy to deliver, readily disseminated and scalable. A novel one-session intervention by Iyadurai et al. 2018, Molecular Psychiatry, resulted in intrusion reduction over the subsequent week. Its feasibility in a different setting and longer-term effects (>1 month) need investigation. We conducted an exploratory open-label pilot randomised controlled trial (RCT) to investigate the feasibility and effects of a brief behavioural intervention to reduce intrusive memories in trauma-exposed patients in a Swedish hospital emergency department (ED). Participants (final N = 41) were randomly allocated to either intervention (including memory reminder cue then visuospatial cognitive task “Tetris” with mental rotation instructions) or active control (podcast) condition within 72 h of presenting to the ED (both conditions using their smartphone). Findings were examined descriptively. We estimated between-group effect sizes for the number of intrusive memories post-intervention at week 1 (primary outcome) and week 5 (secondary outcome). Compared to the control condition, participants in the intervention condition reported fewer intrusive memories of trauma, both at week 1 and week 5. Findings extend the previous evaluation in the UK. The intervention was readily implemented in a different international context, with a mixed trauma sample, with treatment gains maintained at 1 month and associated with some functional improvements. Findings inform future trials to evaluate the capacity of the cognitive task intervention to reduce the occurrence of intrusive memories after traumatic events.
Gray and white matter morphology in substance use disorders: a neuroimaging systematic review and meta-analysis
Authors: Pando-Naude Victor , Toxto Sebastian , Fernandez-Lozano Sofia , Parsons Christine E. , Alcauter Sarael , Garza-Villarreal Eduardo A.
Published: January 2021

Substance use disorders (SUDs) are characterized by a compulsion to seek and consume one or more substances of abuse, with a perceived loss of control and a negative emotional state. Prolonged substance use seems to be associated with morphological changes of multiple neural circuits, in particular the frontal–striatal and limbic pathways. Such neuroadaptations are evident across several substance disorders, but may vary depending on the type of substance, consumption severity and/or other unknown factors. We therefore identified studies investigating the effects of SUDs using volumetric whole-brain voxel-based morphometry (VBM) in gray (GM) and white matter (WM). We performed a systematic review and meta-analysis of VBM studies using the anatomic likelihood estimation (ALE) method implemented in GingerALE (PROSPERO pre-registrationCRD42017071222). Sixty studies met inclusion criteria and were included in the final quantitative meta-analysis, with a total of 614 foci, 94 experiments and 4938 participants. We found convergence and divergence in brain regions and volume effects (higher vs. lower volume) in GM and WM depending on the severity of the consumption pattern and type of substance used. Convergent pathology was evident across substances in GM of the insula, anterior cingulate cortex, putamen, and thalamus, and in WM of the thalamic radiation and internal capsule bundle. Divergent pathology between occasional use (cortical pathology) and addiction (cortical-subcortical pathology) provides evidence of a possible top-down neuroadaptation. Our findings indicate particular brain morphometry alterations in SUDs, which may inform our understanding of disease progression and ultimately therapeutic approaches.
Clinical and genetic differences between bipolar disorder type 1 and 2 in multiplex families
Authors: Guzman-Parra Jose , Streit Fabian , Forstner Andreas J. , Strohmaier Jana , González Maria José , Gil Flores Susana , Cabaleiro Fabeiro Francisco J. , del Río Noriega Francisco , Perez Perez Fermin , Haro González Jesus , Orozco Diaz Guillermo , de Diego-Otero Yolanda , Moreno-Kustner Berta , Auburger Georg , Degenhardt Franziska , Heilmann-Heimbach Stefanie , Herms Stefan , Hoffmann Per , Frank Josef , Foo Jerome C. , Sirignano Lea , Witt Stephanie H. , Cichon Sven , Rivas Fabio , Mayoral Fermín , Nöthen Markus M. , Andlauer Till F. M. , Rietschel Marcella
Published: January 2021

The two major subtypes of bipolar disorder (BD), BD-I and BD-II, are distinguished based on the presence of manic or hypomanic episodes. Historically, BD-II was perceived as a less severe form of BD-I. Recent research has challenged this concept of a severity continuum. Studies in large samples of unrelated patients have described clinical and genetic differences between the subtypes. Besides an increased schizophrenia polygenic risk load in BD-I, these studies also observed an increased depression risk load in BD-II patients. The present study assessed whether such clinical and genetic differences are also found in BD patients from multiplex families, which exhibit reduced genetic and environmental heterogeneity. Comparing 252 BD-I and 75 BD-II patients from the Andalusian Bipolar Family (ABiF) study, the clinical course, symptoms during depressive and manic episodes, and psychiatric comorbidities were analyzed. Furthermore, polygenic risk scores (PRS) for BD, schizophrenia, and depression were assessed. BD-I patients not only suffered from more severe symptoms during manic episodes but also more frequently showed incapacity during depressive episodes. A higher BD PRS was significantly associated with suicidal ideation. Moreover, BD-I cases exhibited lower depression PRS. In line with a severity continuum from BD-II to BD-I, our results link BD-I to a more pronounced clinical presentation in both mania and depression and indicate that the polygenic risk load of BD predisposes to more severe disorder characteristics. Nevertheless, our results suggest that the genetic risk burden for depression also shapes disorder presentation and increases the likelihood of BD-II subtype development.
A simultaneous [11C]raclopride positron emission tomography and functional magnetic resonance imaging investigation of striatal dopamine binding in autism
Authors: Zürcher Nicole R. , Walsh Erin C. , Phillips Rachel D. , Cernasov Paul M. , Tseng Chieh-En J. , Dharanikota Ayarah , Smith Eric , Li Zibo , Kinard Jessica L. , Bizzell Joshua C. , Greene Rachel K. , Dillon Daniel , Pizzagalli Diego A. , Izquierdo-Garcia David , Truong Kinh , Lalush David , Hooker Jacob M. , Dichter Gabriel S.
Published: January 2021

The social motivation hypothesis of autism posits that autism spectrum disorder (ASD) is characterized by impaired motivation to seek out social experience early in life that interferes with the development of social functioning. This framework suggests that impaired mesolimbic dopamine function underlies compromised responses to social rewards in ASD. Although this hypothesis is supported by functional magnetic resonance imaging (fMRI) studies, no molecular imaging study has evaluated striatal dopamine functioning in response to rewards in ASD. Here, we examined striatal functioning during monetary incentive processing in ASD and controls using simultaneous positron emission tomography (PET) and fMRI. Using a bolus + infusion protocol with the D2/D3 dopamine receptor antagonist [11C]raclopride, voxel-wise binding potential (BPND) was compared between groups (controls = 12, ASD = 10) in the striatum. Striatal clusters showing significant between-group BPNDdifferences were used as seeds in whole-brain fMRI general functional connectivity analyses. Relative to controls, the ASD group demonstrated decreased phasic dopamine release to incentives in the bilateral putamen and left caudate, as well as increased functional connectivity between a PET-derived right putamen seed and the precuneus and insula. Within the ASD group, decreased phasic dopamine release in the putamen was related to poorer theory-of-mind skills. Our findings that ASD is characterized by impaired striatal phasic dopamine release to incentives provide support for the social motivation hypothesis of autism. PET-fMRI may be a suitable tool to evaluate novel ASD therapeutics targeting the striatal dopamine system.
Development and external validation of an admission risk prediction model after treatment from early intervention in psychosis services
Authors: Puntis Stephen , Whiting Daniel , Pappa Sofia , Lennox Belinda
Published: January 2021

Early Intervention in psychosis (EIP) teams are the gold standard treatment for first-episode psychosis (FEP). EIP is time-limited and clinicians are required to make difficult aftercare decisions that require weighing up individuals’ wishes for treatment, risk of relapse, and health service capacity. Reliable decision-making tools could assist with appropriate resource allocation and better care. We aimed to develop and externally validate a readmission risk tool for application at the point of EIP discharge. All persons from EIP caseloads in two NHS Trusts were eligible for the study. We excluded those who moved out of the area or were only seen for assessment. We developed a model to predict the risk of hospital admission within a year of ending EIP treatment in one Trust and externally validated it in another. There were n = 831 participants in the development dataset and n = 1393 in the external validation dataset, with 79 (9.5%) and 162 (11.6%) admissions to inpatient hospital, respectively. Discrimination was AUC = 0.76 (95% CI 0.75; 0.77) in the development dataset and AUC = 0.70 (95% CI 0.66; 0.75) in the external dataset. Calibration plots in external validation suggested an underestimation of risk in the lower predicted probabilities and slight overestimation at predicted probabilities in the 0.1–0.2 range (calibration slope = 0.86, 95% CI 0.68; 1.05). Recalibration improved performance at lower predicted probabilities but underestimated risk at the highest range of predicted probabilities (calibration slope = 1.00, 95% CI 0.79; 1.21). We showed that a tool for predicting admission risk using routine data has good performance and could assist clinical decision-making. Refinement of the model, testing its implementation and further external validation are needed.
ACPA decreases non-small cell lung cancer line growth through Akt/PI3K and JNK pathways in vitro
Authors: Boyacıoğlu Özge , Bilgiç Elif , Varan Cem , Bilensoy Erem , Nemutlu Emirhan , Sevim Duygu , Kocaefe Çetin , Korkusuz Petek
Published: January 2021

Therapeutic agents used for non-small cell lung cancer (NSCLC) have limited curative efficacy and may trigger serious adverse effects. Cannabinoid ligands exert antiproliferative effect and induce apoptosis on numerous epithelial cancers. We confirmed that CB1 receptor (CB1R) is expressed in NSCLC cells in this study. Arachidonoylcyclopropylamide (ACPA) as a synthetic, CB1R-specific ligand decreased proliferation rate in NSCLC cells by WST-1 analysis and real-time proliferation assay (RTCA). The half-maximal inhibitory concentration (IC50) dose of ACPA was calculated as 1.39 × 10−12 M. CB1 antagonist AM281 inhibited the antiproliferative effect of ACPA. Flow cytometry and ultrastructural analyzes revealed significant early and late apoptosis with diminished cell viability. Nano-immunoassay and metabolomics data on activation status of CB1R-mediated pro-apoptotic pathways found that ACPA inhibited Akt/PI3K pathway, glycolysis, TCA cycle, amino acid biosynthesis, and urea cycle and activated JNK pathway. ACPA lost its chemical stability after 24 hours tested by liquid chromatography-mass spectrometry (LC–MS/MS) assay. A novel ACPA-PCL nanoparticle system was developed by nanoprecipitation method and characterized. Sustained release of ACPA-PCL nanoparticles also reduced proliferation of NSCLC cells. Our results demonstrated that low dose ACPA and ACPA-PCL nanoparticle system harbor opportunities to be developed as a novel therapy in NSCLC patients that require further in vivo studies beforehand to validate its anticancer effect.
Histone deacetylase 2 regulates ULK1 mediated pyroptosis during acute liver failure by the K68 acetylation site
Authors: Wang Yao , Chen Qian , Jiao Fangzhou , Shi Chunxia , Pei Maohua , Wang Luwen , Gong Zuojiong
Published: January 2021

Pyroptosis is a new necrosis pattern of hepatocyte during liver inflammation in acute liver failure (ALF). Histone deacetylase 2 (HDAC2) is associated with several pathological conditions in the liver system. The aim of this study is to investigate whether knockdown or pharmacological inhibition of HDAC2 could reduce the level of pyroptosis in ALF through ULK1-NLRP3-pyroptosis pathway. The role of HDAC2 on ULK1-NLRP3-pyroptosis pathway during ALF was detected in clinical samples. The mechanism was investigated in transfected cells or in ALF mouse model. The RNA-sequencing results revealed that ULK1 was a negative target regulatory molecule by HDAC2. During the process of pyroptosis, the HDAC2 exerted the antagonistic effect with ULK1 by the K68 acetylation site in L02 cells. Then the role of HDAC2 on ULK1-NLRP3-pyroptosis pathway in ALF mouse model was also detected. Moreover, the related molecules to ULK1-NLRP3-pyroptosis pathway were verified different expression in normal health donors and clinical ALF patients. HDAC2 in hepatocytes plays a pivotal role in an ULK1-NLRP3 pathway driven auto-amplification of pyroptosis in ALF. One of the important mechanisms is that inhibition HDAC2 to reduce pyroptosis may be by modulating the K68 lysine site of ULK1.
Suppressing BCL-XL increased the high dose androgens therapeutic effect to better induce the Enzalutamide-resistant prostate cancer autophagic cell death
Authors: Xiang Zhendong , Sun Yin , You Bosen , Zhang Meng , Huang Chiping , Yu Junfeng , You Xiangyun , Wu Denglong , Chang Chawnshang
Published: January 2021

Most patients with advanced prostate cancer (PCa) initially respond well to androgen deprivation therapy (ADT) with antiandrogens, but most of them eventually become resistant to ADT. Here, we found that the antiandrogen Enzalutamide-resistant (EnzR) PCa cells can be suppressed by hyper-physiological doses of the androgen DHT. Mechanism dissection indicates that while androgens/androgen receptor (AR) can decrease BCL-2 expression to induce cell death, yet they can also simultaneously increase anti-apoptosis BCL-XL protein expression via decreasing its potential E3 ubiquitin ligase, PARK2, through transcriptionally increasing the miR-493-3p expression to target PARK2. Thus, targeting the high dose DHT/AR/miR-493-3p/PARK2/BCL-XL signaling with BCL-XL-shRNA can increase high-dose-DHT effect to better suppress EnzR cell growth via increasing the autophagic cell death. A preclinical study using in vivo mouse model also validated that suppressing BCL-XL led to enhance high dose DHT effect to induce PCa cell death. The success of human clinical trials in the future may help us to develop a novel therapy using high dose androgens to better suppress CRPC progression.
Homotypic CARD-CARD interaction is critical for the activation of NLRP1 inflammasome
Authors: Xu Zhihao , Zhou Ying , Liu Muziying , Ma Huan , Sun Liangqi , Zahid Ayesha , Chen Yulei , Zhou Rongbin , Cao Minjie , Wu Dabao , Zhao Weidong , Li Bofeng , Jin Tengchuan
Published: January 2021

Cytosolic inflammasomes are supramolecular complexes that are formed in response to intracellular pathogens and danger signals. However, as to date, the detailed description of a homotypic caspase recruitment domain (CARD) interaction between NLRP1 and ASC has not been presented. We found the CARD–CARD interaction between purified NLRP1CARD and ASCCARD experimentally and the filamentous supramolecular complex formation in an in vitro proteins solution. Moreover, we determined a high-resolution crystal structure of the death domain fold of the human ASCCARD. Mutational and structural analysis revealed three conserved interfaces of the death domain superfamily (Type I, II, and III), which mediate the assembly of the NLRP1CARD/ASCCARD complex. In addition, we validated the role of the three major interfaces of CARDs in assembly and activation of NLRP1 inflammasome in vitro. Our findings suggest a Mosaic model of homotypic CARD interactions for the activation of NLRP1 inflammasome. The Mosaic model provides insights into the mechanisms of inflammasome assembly and signal transduction amplification.
Discovery of a new molecule inducing melanoma cell death: dual AMPK/MELK targeting for novel melanoma therapies
Authors: Jaune Emilie , Cavazza Elisa , Ronco Cyril , Grytsai Oleksandr , Abbe Patricia , Tekaya Nedra , Zerhouni Marwa , Beranger Guillaume , Kaminski Lisa , Bost Frédéric , Gesson Maeva , Tulic Meri , Hofman Paul , Ballotti Robert , Passeron Thierry , Botton Thomas , Benhida Rachid , Rocchi Stéphane
Published: January 2021

In the search of biguanide-derived molecules against melanoma, we have discovered and developed a series of bioactive products and identified the promising new compound CRO15. This molecule exerted anti-melanoma effects on cells lines and cells isolated from patients including the ones derived from tumors resistant to BRAF inhibitors. Moreover, CRO15 was able to decrease viability of cells lines from a broad range of cancer types. This compound acts by two distinct mechanisms. First by activating the AMPK pathway induced by a mitochondrial disorder. Second by inhibition of MELK kinase activity, which induces cell cycle arrest and activation of DNA damage repair pathways by p53 and REDD1 activation. All of these mechanisms activate autophagic and apoptotic processes resulting in melanoma cell death. The strong efficacy of CRO15 to reduce the growth of melanoma xenograft sensitive or resistant to BRAF inhibitors opens interesting perspective.
The redox language in neurodegenerative diseases: oxidative post-translational modifications by hydrogen peroxide
Authors: Lee Yew Mun , He Weifeng , Liou Yih-Cherng
Published: January 2021

Neurodegenerative diseases, a subset of age-driven diseases, have been known to exhibit increased oxidative stress. The resultant increase in reactive oxygen species (ROS) has long been viewed as a detrimental byproduct of many cellular processes. Despite this, therapeutic approaches using antioxidants were deemed unsuccessful in circumventing neurodegenerative diseases. In recent times, it is widely accepted that these toxic by-products could act as secondary messengers, such as hydrogen peroxide (H2O2), to drive important signaling pathways. Notably, mitochondria are considered one of the major producers of ROS, especially in the production of mitochondrial H2O2. As a secondary messenger, cellular H2O2can initiate redox signaling through oxidative post-translational modifications (oxPTMs) on the thiol group of the amino acid cysteine. With the current consensus that cellular ROS could drive important biological signaling pathways through redox signaling, researchers have started to investigate the role of cellular ROS in the pathogenesis of neurodegenerative diseases. Moreover, mitochondrial dysfunction has been linked to various neurodegenerative diseases, and recent studies have started to focus on the implications of mitochondrial ROS from dysfunctional mitochondria on the dysregulation of redox signaling. Henceforth, in this review, we will focus our attention on the redox signaling of mitochondrial ROS, particularly on mitochondrial H2O2, and its potential implications with neurodegenerative diseases.
Legumain promotes tubular ferroptosis by facilitating chaperone-mediated autophagy of GPX4 in AKI
Authors: Chen Chuan’ai , Wang Dekun , Yu Yangyang , Zhao Tianyuan , Min Ningning , Wu Yan , Kang Lichun , Zhao Yong , Du Lingfang , Zhang Mianzhi , Gong Junbo , Zhang Zhujun , Zhang Yuying , Mi Xue , Yue Shijing , Tan Xiaoyue
Published: January 2021

Legumain is required for maintenance of normal kidney homeostasis. However, its role in acute kidney injury (AKI) is still unclear. Here, we induced AKI by bilateral ischemia-reperfusion injury (IRI) of renal arteries or folic acid in lgmnWT and lgmnKO mice. We assessed serum creatinine, blood urea nitrogen, histological indexes of tubular injury, and expression of KIM-1 and NGAL. Inflammatory infiltration was evaluated by immunohistological staining of CD3 and F4/80, and expression of TNF-α, CCL-2, IL-33, and IL-1α. Ferroptosis was evaluated by Acsl4, Cox-2, reactive oxygen species (ROS) indexes H2DCFDA and DHE, MDA and glutathione peroxidase 4 (GPX4). We induced ferroptosis by hypoxia or erastin in primary mouse renal tubular epithelial cells (mRTECs). Cellular survival, Acsl4, Cox-2, LDH release, ROS, and MDA levels were measured. We analyzed the degradation of GPX4 through inhibition of proteasomes or autophagy. Lysosomal GPX4 was assessed to determine GPX4 degradation pathway. Immunoprecipitation (IP) was used to determine the interactions between legumain, GPX4, HSC70, and HSP90. For tentative treatment, RR-11a was administrated intraperitoneally to a mouse model of IRI-induced AKI. Our results showed that legumain deficiency attenuated acute tubular injury, inflammation, and ferroptosis in either IRI or folic acid-induced AKI model. Ferroptosis induced by hypoxia or erastin was dampened in lgmnKO mRTECs compared with lgmnWT control. Deficiency of legumain prevented chaperone-mediated autophagy of GPX4. Results of IP suggested interactions between legumain, HSC70, HSP90, and GPX4. Administration of RR-11a ameliorated ferroptosis and renal injury in the AKI model. Together, our data indicate that legumain promotes chaperone-mediated autophagy of GPX4 therefore facilitates tubular ferroptosis in AKI.
Galectin-1 accelerates high-fat diet-induced obesity by activation of peroxisome proliferator-activated receptor gamma (PPARγ) in mice
Authors: Baek Jung-Hwan , Kim Da-Hyun , Lee Jaegyeong , Kim Seok-Jun , Chun Kyung-Hee
Published: January 2021

Galectin-1 contains a carbohydrate-recognition domain (CRD) as a member of the lectin family. Here, we investigated whether galectin-1 regulates adipogenesis and lipid accumulation. Galectin-1 mRNA is highly expressed in metabolic tissues such as the muscle and adipose tissues. Higher mRNA expression of galectin-1 was detected in white adipose tissues (WATs) of mice that were fed a high-fat diet (HFD) than in those of mice fed a normal-fat diet (NFD). Protein expression of galectin-1 also increased during adipocyte differentiation. Galectin-1 silencing inhibited the differentiation of 3T3-L1 cells and the expression of lipogenic factors, such as PPARγ, C/EBPα, FABP4, and FASN at both mRNA and protein levels. Lactose, an inhibitor by the binding with CRD of galectin-1 in extracellular matrix, did not affect adipocyte differentiation. Galectin-1 is localized in multiple cellular compartments in 3T3-L1 cells. However, we found that DMI (dexamethasone, methylisobutylxanthine, insulin) treatment increased its nuclear localization. Interestingly, galectin-1 interacted with PPARγ. Galectin-1 overexpression resulted in increased PPARγ expression and transcriptional activity. Furthermore, we prepared galectin-1-knockout (Lgals1−/−) mice and fed a 60% HFD. After 10 weeks, Lgals1−/− mice exhibited lower body weight and gonadal WAT (gWAT) mass than wild-type mice. Fasting glucose level was also lower in Lgals1−/−mice than that in wild-type mice. Moreover, lipogenic genes were significantly downregulated in the gWATs and liver tissues from Lgals1−/− mice. Pro-inflammatory cytokines, such as CCL2, CCL3, TNFα, and F4/80, as well as macrophage markers, were also drastically downregulated in the gWATs and liver tissues of Lgals1−/− mice. In addition, Lgals1−/−mice showed elevated expression of genes involved in thermogenesis in the brown adipose tissue. Collectively, galectin-1 exacerbates obesity of mice fed HFD by increment of PPARγ expression and activation. Our findings suggest that galectin-1 could be a potential therapeutic target for obesity and needed further study for clinical application.
Taurocholic acid inhibits the response to interferon-α therapy in patients with HBeAg-positive chronic hepatitis B by impairing CD8+ T and NK cell function
Authors: Xun Zhen , Lin Jinpiao , Yu Qingqing , Liu Can , Huang Jinlan , Shang Hongyan , Guo Jianhui , Ye Yuchen , Wu Wennan , Zeng Yongbin , Wu Songhang , Xu Siyi , Chen Tianbin , Chen Jing , Ou Qishui
Published: January 2021

Pegylated interferon-alpha (PegIFNα) therapy has limited effectiveness in hepatitis B e-antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. However, the mechanism underlying this failure is poorly understood. We aimed to investigate the influence of bile acids (BAs), especially taurocholic acid (TCA), on the response to PegIFNα therapy in CHB patients. Here, we used mass spectrometry to determine serum BA profiles in 110 patients with chronic HBV infection and 20 healthy controls (HCs). We found that serum BAs, especially TCA, were significantly elevated in HBeAg-positive CHB patients compared with those in HCs and patients in other phases of chronic HBV infection. Moreover, serum BAs, particularly TCA, inhibited the response to PegIFNα therapy in HBeAg-positive CHB patients. Mechanistically, the expression levels of IFN-γ, TNF-α, granzyme B, and perforin were measured using flow cytometry to assess the effector functions of immune cells in patients with low or high BA levels. We found that BAs reduced the number and proportion and impaired the effector functions of CD3+CD8+ T cells and natural killer (NK) cells in HBeAg-positive CHB patients. TCA in particular reduced the frequency and impaired the effector functions of CD3+CD8+ T and NK cells in vitro and in vivo and inhibited the immunoregulatory activity of IFN-α in vitro. Thus, our results show that BAs, especially TCA, inhibit the response to PegIFNα therapy by impairing the effector functions of CD3+CD8+ T and NK cells in HBeAg-positive CHB patients. Our findings suggest that targeting TCA could be a promising approach for restoring IFN-α responsiveness during CHB treatment.
Clinical validation of an artificial intelligence-based diabetic retinopathy screening tool for a national health system
Authors: Arenas-Cavalli José Tomás , Abarca Ignacio , Rojas-Contreras Maximiliano , Bernuy Fernando , Donoso Rodrigo
Published: January 2021

Objective

To evaluate the accuracy and validity of an automated diabetic retinopathy (DR) screening tool (DART, TeleDx, Santiago, Chile) that uses artificial intelligence to analyze ocular fundus photographs for potential implementation in the national Chilean DR screening programme.

Method

This was an observational study of 1123 diabetic eye exams using a validation protocol designed by the commission of the Chilean Ministry of Health personnel and retina specialists.

Results

Receiver operating characteristic (ROC) analysis indicated a sensitivity of 94.6% (95% CI: 90.9–96.9%), specificity of 74.3% (95% CI: 73.3–75%), and negative predictive value of 98.1% (95% CI: 96.8–98.9%) for the automated tool at the optimal operating point for DR screening. The area under the ROC curve was 0.915.

Conclusions

The results of this study suggest that DART is a valid tool that could be implemented in a heterogeneous health network such as the Chilean system.
Synthesis of molecular metallic barium superhydride: pseudocubic BaH12
Authors: Chen Wuhao , Semenok Dmitrii V. , Kvashnin Alexander G. , Huang Xiaoli , Kruglov Ivan A. , Galasso Michele , Song Hao , Duan Defang , Goncharov Alexander F. , Prakapenka Vitali B. , Oganov Artem R. , Cui Tian
Published: January 2021

Following the discovery of high-temperature superconductivity in the La–H system, we studied the formation of new chemical compounds in the barium-hydrogen system at pressures from 75 to 173 GPa. Using in situ generation of hydrogen from NH3BH3, we synthesized previously unknown superhydride BaH12 with a pseudocubic (fcc) Ba sublattice in four independent experiments. Density functional theory calculations indicate close agreement between the theoretical and experimental equations of state. In addition, we identified previously known P6/mmm-BaH2 and possibly BaH10 and BaH6 as impurities in the samples. Ab initio calculations show that newly discovered semimetallic BaH12 contains H2 and H3– molecular units and detached H12 chains which are formed as a result of a Peierls-type distortion of the cubic cage structure. Barium dodecahydride is a unique molecular hydride with metallic conductivity that demonstrates the superconducting transition around 20 K at 140 GPa.
Construction and integration of three de novo Japanese human genome assemblies toward a population-specific reference
Authors: Takayama Jun , Tadaka Shu , Yano Kenji , Katsuoka Fumiki , Gocho Chinatsu , Funayama Takamitsu , Makino Satoshi , Okamura Yasunobu , Kikuchi Atsuo , Sugimoto Sachiyo , Kawashima Junko , Otsuki Akihito , Sakurai-Yageta Mika , Yasuda Jun , Kure Shigeo , Kinoshita Kengo , Yamamoto Masayuki , Tamiya Gen
Published: January 2021

The complete human genome sequence is used as a reference for next-generation sequencing analyses. However, some ethnic ancestries are under-represented in the reference genome (e.g., GRCh37) due to its bias toward European and African ancestries. Here, we perform de novo assembly of three Japanese male genomes using > 100× Pacific Biosciences long reads and Bionano Genomics optical maps per sample. We integrate the genomes using the major allele for consensus and anchor the scaffolds using genetic and radiation hybrid maps to reconstruct each chromosome. The resulting genome sequence, JG1, is contiguous, accurate, and carries the Japanese major allele at most loci. We adopt JG1 as the reference for confirmatory exome re-analyses of seven rare-disease Japanese families and find that re-analysis using JG1 reduces total candidate variant calls versus GRCh37 while retaining disease-causing variants. These results suggest that integrating multiple genomes from a single population can aid genome analyses of that population.
Intratumoural immune heterogeneity as a hallmark of tumour evolution and progression in hepatocellular carcinoma
Authors: Nguyen Phuong H. D. , Ma Siming , Phua Cheryl Z. J. , Kaya Neslihan A. , Lai Hannah L. H. , Lim Chun Jye , Lim Jia Qi , Wasser Martin , Lai Liyun , Tam Wai Leong , Lim Tony K. H. , Wan Wei Keat , Loh Tracy , Leow Wei Qiang , Pang Yin Huei , Chan Chung Yip , Lee Ser Yee , Cheow Peng Chung , Toh Han Chong , Ginhoux Florent , Iyer Shridhar , Kow Alfred W. C. , Young Dan Yock , Chung Alexander , Bonney Glen K. , Goh Brian K. P. , Albani Salvatore , Chow Pierce K. H. , Zhai Weiwei , Chew Valerie
Published: January 2021

The clinical relevance of immune landscape intratumoural heterogeneity (immune-ITH) and its role in tumour evolution remain largely unexplored. Here, we uncover significant spatial and phenotypic immune-ITH from multiple tumour sectors and decipher its relationship with tumour evolution and disease progression in hepatocellular carcinomas (HCC). Immune-ITH is associated with tumour transcriptomic-ITH, mutational burden and distinct immune microenvironments. Tumours with low immune-ITH experience higher immunoselective pressure and escape via loss of heterozygosity in human leukocyte antigens and immunoediting. Instead, the tumours with high immune-ITH evolve to a more immunosuppressive/exhausted microenvironment. This gradient of immune pressure along with immune-ITH represents a hallmark of tumour evolution, which is closely linked to the transcriptome-immune networks contributing to disease progression and immune inactivation. Remarkably, high immune-ITH and its transcriptomic signature are predictive for worse clinical outcome in HCC patients. This in-depth investigation of ITH provides evidence on tumour-immune co-evolution along HCC progression.
Dynamics of soliton self-injection locking in optical microresonators
Authors: Voloshin Andrey S. , Kondratiev Nikita M. , Lihachev Grigory V. , Liu Junqiu , Lobanov Valery E. , Dmitriev Nikita Yu. , Weng Wenle , Kippenberg Tobias J. , Bilenko Igor A.
Published: January 2021

Soliton microcombs constitute chip-scale optical frequency combs, and have the potential to impact a myriad of applications from frequency synthesis and telecommunications to astronomy. The demonstration of soliton formation via self-injection locking of the pump laser to the microresonator has significantly relaxed the requirement on the external driving lasers. Yet to date, the nonlinear dynamics of this process has not been fully understood. Here, we develop an original theoretical model of the laser self-injection locking to a nonlinear microresonator, i.e., nonlinear self-injection locking, and construct state-of-the-art hybrid integrated soliton microcombs with electronically detectable repetition rate of 30 GHz and 35 GHz, consisting of a DFB laser butt-coupled to a silicon nitride microresonator chip. We reveal that the microresonator’s Kerr nonlinearity significantly modifies the laser diode behavior and the locking dynamics, forcing laser emission frequency to be red-detuned. A novel technique to study the soliton formation dynamics as well as the repetition rate evolution in real-time uncover non-trivial features of the soliton self-injection locking, including soliton generation at both directions of the diode current sweep. Our findings provide the guidelines to build electrically driven integrated microcomb devices that employ full control of the rich dynamics of laser self-injection locking, key for future deployment of microcombs for system applications.
Anti-senescent drug screening by deep learning-based morphology senescence scoring
Authors: Kusumoto Dai , Seki Tomohisa , Sawada Hiromune , Kunitomi Akira , Katsuki Toshiomi , Kimura Mai , Ito Shogo , Komuro Jin , Hashimoto Hisayuki , Fukuda Keiichi , Yuasa Shinsuke
Published: January 2021

Advances in deep learning technology have enabled complex task solutions. The accuracy of image classification tasks has improved owing to the establishment of convolutional neural networks (CNN). Cellular senescence is a hallmark of ageing and is important for the pathogenesis of ageing-related diseases. Furthermore, it is a potential therapeutic target. Specific molecular markers are used to identify senescent cells. Moreover senescent cells show unique morphology, which can be identified. We develop a successful morphology-based CNN system to identify senescent cells and a quantitative scoring system to evaluate the state of endothelial cells by senescence probability output from pre-trained CNN optimised for the classification of cellular senescence, Deep Learning-Based Senescence Scoring System by Morphology (Deep-SeSMo). Deep-SeSMo correctly evaluates the effects of well-known anti-senescent reagents. We screen for drugs that control cellular senescence using a kinase inhibitor library by Deep-SeSMo-based drug screening and identify four anti-senescent drugs. RNA sequence analysis reveals that these compounds commonly suppress senescent phenotypes through inhibition of the inflammatory response pathway. Thus, morphology-based CNN system can be a powerful tool for anti-senescent drug screening.