bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient microwave-assisted extraction of salidroside from Rhodiola crenulata
Authors: Liu Rui , Guo Chen , Feng Mei , Liu Chun-Zhao
Published: January 2021

A rapid microwave-assisted extraction (MAE) method was established to extract commercially important salidroside from dry plant materials of Rhodiola crenulata. Several parameters such as extraction time, solid/liquid ratio, extraction temperature and solvent concentration were investigated for efficient salidroside extraction. The estimated maximum salidroside extraction ratio based on parameter optimization using response surface methodology (RSM) reached 2.17% (w/w) in 20 min at optimum conditions of 90 °C, 60% aqueous ethanol and solid to liquid ratio of 2 g/100 mL, which was confirmed to the experimental data. Compared with ultrasonic assistant extraction method (UAE) and heat reflux extraction method (HRE), MAE was the most efficient and effective method in the extraction of salidroside from the dry plant materials. The mechanism on the extraction enhancement using MAE was elucidated further using fourier transform infrared spectroscopy (FTIR) and light microscope.
Incidence of catastrophic healthcare expenditure and its main determinants in Mexican households caring for a person with a mental disorder
Authors: Diaz-Castro Lina , Cabello-Rangel Héctor , Pineda-Antúnez Carlos , Pérez de León Alejandra
Published: January 2021

Background

There are few studies on the impact of out-of-pocket mental health care expenditures and sociodemographic factors on the probability of Mexican households to incur catastrophic healthcare expenditures (CHE).

Objective

The goal of the present study was to estimate the incidence of CHE and its main determinants among the households of persons with mental disorders (MD) in Mexico.

Methods

A cross-sectional survey was conducted, including 387 households of persons with MD. The estimation of the CHE was obtained by the health expenditure distribution method. A Logistic Regression (LR) was used to identify the determinants of probability variation of CHE occurrence. Since we expected a proportion of CHE between 20% and 80%, we assume linearity in the probability function, therefore we additionally used an Ordinary Least Squares (OLS) model.

Results

In our sample, the incidence of CHE was 34.8%. The two mental illnesses most frequently associated with CHE were schizophrenia and hyperactive disorder (35.5% and 32.6% of CHE cases, respectively). The regression coefficients showed that for each unit (US$53.77) increase in income, the probability of CHE was reduced by 8.6%, while for each unit increase in hospitalization or medication expenditures, the probability of CHE increased by 12.9% or 19%, respectively. For each additional household member, the probability of CHE increased by 3%, and households with a male patient had a 7% greater probability of CHE.

Conclusion

Household income, household size, hospitalization and medication expenses, and sex of the patient were significant predictors of CHE for households caring for a person with MD.
Minimal impact of selective susceptibility reporting on the use of piperacillin-tazobactam for Escherichia coli and Klebsiella bacteremia
Authors: Zahlanie Yorgo , Hall Brenton C. , Wei Wenjing , Mang Norman S. , Ortwine Jessica K. , Anderson Shelby , Morgan Kristi , Guzman Tamara P. , Hynan Linda S. , Prokesch Bonnie C.
Published: January 2021

Selective cascade reporting of antibiotic susceptibilities did not have a significant impact on de-escalation from piperacillin-tazobactam (PT), duration of PT use, length of stay, or rates of acute kidney injury and Clostridioides difficile infection in patients with positive monomicrobial blood cultures with either Escherichia coli or Klebsiella spp.
Safety at Sea during the Industrial Revolution
Authors: Kelly Morgan , Ó Gráda Cormac , Solar Peter M.
Published: January 2021

Shipping, central to the rise of the Atlantic economies, was an extremely hazardous activity. Between the 1780s and 1820s, a safety revolution occurred that saw shipping losses and insurance rates on oceanic routes almost halved thanks to steady improvements in shipbuilding and navigation. Copper sheathing, iron reinforcing, and flush decks were the major innovations in shipbuilding. Navigation improved, not through chronometers, which remained too expensive and unreliable for general use, but through radically improved charts, accessible manuals of basic navigational techniques, and improved shore-based navigational aids.

“Curse thee, thou quadrant!” dashing it to the deck, “no longer will I guide my earthly way by thee; the level ship’s compass, and the level dead-reckoning, by log and by line; these shall conduct me, and show me my place on the sea.”

Captain Ahab inMoby Dick,Ch. CXIII
Mechanical circulatory support in paediatric population
Authors: Melamed Naomi , Iddawela Sashini , Poole Grace Olivia Jane , Ajibade Ayomikun , Harky Amer
Published: January 2021

Extra-corporeal membrane oxygenation is a life-saving modality to support the cardiac and/or pulmonary system as a form of life support in resuscitation, post-cardiotomy, as a bridge to cardiac transplantation and in respiratory failure. Its use in the paediatric and neonatal population has proven incredibly useful. However, extra-corporeal membrane oxygenation is also associated with a greater rate of mortality and complications, particularly in those with co-morbidities. As a result, interventions such as ventricular assist devices have been trialled in these patients. In this review, we provide a comprehensive analysis of the current literature on extra-corporeal membrane oxygenation for cardiac support in the paediatric and neonatal population. We evaluate its effectiveness in comparison to other forms of mechanical circulatory support and focus on areas for future development.
Individual and joint effects of genetic polymorphisms in microRNA-machinery genes on congenital heart disease susceptibility
Authors: Borghini Andrea , Vecoli Cecilia , Mercuri Antonella , Turchi Stefano , Andreassi Maria Grazia
Published: January 2021

Single-nucleotide polymorphisms in miRNA-machinery genes may alter the biogenesis of miRNAs affecting disease susceptibility. In this case–control study, we aimed to evaluate the impact of three single-nucleotide polymorphisms (DICER rs1057035, DROSHA rs10719, and XPO5 rs11077) and their combined effect in a genetic risk score model on congenital heart disease (CHD) risk. A total of 639 participants was recruited, including 125 patients with CHD (65 males; age 9.2 ± 10 years) and 514 healthy controls (289 males; age 15.8 ± 18 years). Genotyping of polymorphisms in miRNA-machinery genes was performed using a TaqMan®SNP genotyping assay. A genetic risk score was calculated by summing the number of risk alleles of selected single-nucleotide polymorphisms. There was a significantly increased risk of CHD in patients with XPO5 rs11077 CC genotype as compared to AC heterozygote and AA homozygote patients (ORadjusted = 1.7; 95% CI: 1.1–2.8; p = 0.018). A clear tendency to significance was also found for DROSHA rs10719 AA genotype and CHD risk for both codominant and recessive models (ORadjusted = 1.8; 95% CI: 0.91–3.8; p = 0.09 and ORadjusted = 1.9; 95% CI: 0.92–4; p = 0.08, respectively). The resulting genetic risk score predicted a 1.73 risk for CHD per risk allele (95% CI: 1.2–2.5; p = 0.002). Subjects in the top tertile of genetic risk score were estimated to have more than three-fold increased risk of CHD compared with those in the bottom tertile (ORadjusted = 3.52; 95% CI: 1.4–9; p = 0.009). Our findings show that the genetic variants in miRNA-machinery genes might participate in the development of CHD.
Exploring the Factor Structure of the NIH Toolbox Cognition Battery in a Large Sample of 8-Year-Old Children in Aotearoa New Zealand
Authors: Neumann Denise , Peterson Elizabeth R. , Underwood Lisa , Morton Susan M.B. , Waldie Karen E.
Published: January 2021

Objective:

The objective of this study was to derive a factor structure of the measures of the National Institutes of Health (NIH) Toolbox Cognition Battery (CB) that is representative of cognitive abilities in a large ethnically diverse cohort of 8-year-old children in Aotearoa New Zealand.

Methods:

Our sample comprised of 4298 8-year-old children from the Growing Up in New Zealand study. We conducted exploratory and confirmatory factor analysis for the NIH Toolbox CB measures to discover the best-fitting factor structure in our sample. Measurement invariance of the identified model was tested across child’s gender, socio-economic status (SES), and ethnicity.

Results:

A three-dimensional factor structure was identified, with one factor of Crystallised Cognition (Reading and Vocabulary), and two distinguished factors of fluid cognition: Fluid Cognition I (Attention/Inhibitory Control, Processing Speed, and Cognitive Flexibility) and Fluid Cognition II (Working Memory, Episodic Memory). The results demonstrate excellent model fit, but reliability of the factors was low. Measurement invariance was confirmed for child’s gender. We found configural, but neither metric nor scalar, invariance across SES and the four major ethnic groups: European, Māori, Pacific Peoples, and Asian.

Conclusion:

Our findings show that, at the age of 8 years, fluid abilities are more strongly associated with one another than with crystallised abilities and that fluid abilities need to be further differentiated. This dimensional structure allows for comparisons across child’s gender, but evaluations across SES and ethnicity within the Aotearoa New Zealand context must be conducted with caution. We recommend using raw scores of the individual NIH Toolbox CB measures in future research.
Resilience to economic shrinking in an emerging economy: the role of social capabilities in Indonesia, 1950–2015
Authors: Andersson Martin , Axelsson Tobias , Palacio Andrés
Published: January 2021

Economic history has recently emphasised the impact of economic shrinking on long-term economic growth, but economic theories do not provide explanations for how and why some countries avoid economic shrinking. In this case study of institutional change in post-independence Indonesia, we examine how the country managed to reduce the frequency of shrinking during the authoritarian regime and beyond. We argue that the state's autonomy, measured by macroeconomic policymaking, and accountability, measured by food security, were two key social capabilities that enabled Indonesia to reduce the frequency of economic shrinking. During this period, the ‘doorstep conditions’ for the transition into a democracy and stable economic growth emerged. More specifically, Indonesia managed to diversify its revenue base and make public resources more available for the broader common good. Loosening the connection between macroeconomic policymaking and elites opened up greater opportunities for the emergence of private enterprises. However, to date, the country is still far from a full-fledged open access society.
Pre-Post Effects of the Psychoeducational, Autism-Specific Parent Training FAUT-E
Authors: Medda Juliane E. , Kitzerow Janina , Schlitt Sabine , Berndt Kerstin , Schwenck Christina , Uhlmann Lorenz , Freitag Christine M.
Published: January 2021

Abstract. Objective: Psychoeducational parent training is an economic way to provide care for parents of children newly diagnosed with an autism spectrum disorder (ASD). This study explores pre-post effect sizes of the manualized autism-specific parent training FAUT-E (Frankfurter Autismus-Elterntraining). Method: Two behaviorally trained therapists worked with 6–10 parents in eight group sessions. Twenty-four parents of 24 children with ASD participated in the study. Outcomes were child- and parent-related measures obtained at T0 (first measurement), T1 (second measurement), T2 (postintervention), and T3 (3 months after intervention). Results: Children showed improved behavior in the parent-rated Aberrant Behavior Checklist (ABC) total score after therapy ( p = .001; ES T1T2 = .73) and at T3 ( p = .018; ES T1-T3 = –.51), and a lower intensity of parent-rated problem behavior at T3 ( p = .031; ES T1–T3 = –.46). Parental measures did not change. Conclusions: This study found medium pre-post effects on the child’s behavior by FAUT-E between T1 and T2/T3; these were not observed between the measurements T0–T1. FAUT-E was easy to implement and did not increase parental stress. This is in line with results of studies on other training programs to teach parents to use effective behavioral strategies with ASD.
Früherkennung von Entwicklungsstörungen: Kanonisches Lallen (k)‌ein diagnostischer Marker‍(!)?
Authors: Lang Sigrun , Zhang Dajie , Poustka Luise , Bartl-Pokorny Katrin D. , Pokorny Florian B. , Bölte Sven , Sachse Steffi , Mani Nivedita , Fox-Boyer Annette V. , Hartung Martin , Einspieler Christa , Marschik Peter B.
Published: January 2021

Zusammenfassung. Theoretischer Hintergrund: Forschungsergebnisse zum frühen Spracherwerb bei Kindern mit spät erkannten Entwicklungsstörungen sind inkonsistent und angesichts unterschiedlicher Forschungsparadigmen und Definitionen nur bedingt vergleichbar. Fragestellung: Ziel dieser Übersichtsarbeit ist es, das Potenzial früher verbaler Fähigkeiten, vor allem des kanonischen Lallens, als Marker zur Früherkennung von Autismus-Spektrum-Störung, Rett-Syndrom und Fragilem-X-Syndrom zu beschreiben. Methode: Übersichtsarbeit über retrospektive und prospektive Studien zu frühen verbalen Fähigkeiten in der Prodromalphase dieser Störungsbilder. Ergebnisse: Einige Kinder mit spät erkannten Entwicklungsstörungen erwerben das kanonische Lallen nach dem kritischen Zeitfenster von 6 bis 10 Monaten und/oder haben oft qualitative Veränderungen in ihren Lautäußerungen. Diskussion und Schlussfolgerung: Eine abweichende Entwicklung des kanonischen Lallens kann auf spätere atypische Entwicklung hinweisen. Als funktioneller Marker für die spezifische Früherkennung von Entwicklungsstörungen scheint dieser Erwerbsmeilenstein jedoch nicht geeignet. Linguistische und signalbasierte Detailanalysen frühkindlicher Vokalisationen könnten zukünftig einen entscheidenden Beitrag hierzu leisten.
Struktur und Funktion – Frühkindliche Entwicklung und Früherkennung von Entwicklungsstörungen
Authors: Marschik Peter B. , Freilinger Michael
Published: January 2021

Zusammenfassung. Es werden Themen der kindlichen Entwicklung vom Fötus bis hin zum Schulalter ausgeführt: Beginnend bei fötaler Motorik und dem Entstehen menschlichen Verhaltens, über Entwicklungsverläufe bei Frühgeburtlichkeit oder permanenter Hörstörung, sprachspezifische Marker zur Früherkennung von Neuroentwicklungsstörungen, bis hin zu neurostrukturellen Besonderheiten bei Autismus Spektrum Störung.
Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity
Authors: Fang Xing , Jiang Shujun , Wang Jiangong , Bai Yu , Kim Chung Sub , Blake David , Weintraub Neal L. , Lei Yun , Lu Xin-Yun
Published: January 2021

Previous studies have shown that AgRP neurons in the arcuate nucleus (ARC) respond to energy deficits and play a key role in the control of feeding behavior and metabolism. Here, we demonstrate that chronic unpredictable stress, an animal model of depression, decreases spontaneous firing rates, increases firing irregularity and alters the firing properties of AgRP neurons in both male and female mice. These changes are associated with enhanced inhibitory synaptic transmission and reduced intrinsic neuronal excitability. Chemogenetic inhibition of AgRP neurons increases susceptibility to subthreshold unpredictable stress. Conversely, chemogenetic activation of AgRP neurons completely reverses anhedonic and despair behaviors induced by chronic unpredictable stress. These results indicate that chronic stress induces maladaptive synaptic and intrinsic plasticity, leading to hypoactivity of AgRP neurons and subsequently causing behavioral changes. Our findings suggest that AgRP neurons in the ARC are a key component of neural circuitry involved in mediating depression-related behaviors and that increasing AgRP neuronal activity coule be a novel and effective treatment for depression.
Metformin exhibits antiproliferation activity in breast cancer via miR-483-3p/METTL3/m6A/p21 pathway
Authors: Cheng Lin , Zhang Xu , Huang Yu-Zhou , Zhu Yu-Lan , Xu Ling-Yun , Li Zhi , Dai Xin-Yuan , Shi Liang , Zhou Xu-Jie , Wei Ji-Fu , Ding Qiang
Published: January 2021

Evidence suggests that metformin might be a potential candidate for breast cancer treatment. Yet, its relevant molecular mechanisms remain to be fully investigated. We found that metformin could suppress the N6-methyladenosine (m6A) level in breast cancer cells significantly. The latter has an essential role in breast cancer progression and is newly considered as a therapeutic target. In this study, we measured the m6A level by m6A colorimetric analysis and dot blot assay. We then performed qRT-PCR, western blot, MeRIP, dual-luciferase reporter assay, and others to explore the m6A-dependent pathway associated with metformin. In vivo effect of metformin was investigated using a mouse tumorigenicity model. In addition, breast cancer and normal tissues were used to determine the role of METTL3 in breast cancer. Metformin could reduce the m6A level via decreasing METTL3 expression mediated by miR-483-3p in breast cancer. METTL3 is known to be able to promote breast cancer cell proliferation by regulating the p21 expression by an m6A-dependent manner. Metformin can take p21 as the main target to inhibit such effect. To specify, this study exhibited that metformin can inhibit breast cancer cell proliferation through the pathway miR-483-3p/METTL3/m6A/p21. Our findings suggest that METTL3 may be considered as a potential therapeutic target of metformin for breast cancer.
Feedback activation of STAT3 limits the response to PI3K/AKT/mTOR inhibitors in PTEN-deficient cancer cells
Authors: Wang Jian , Lv Xiaoye , Guo Xiutian , Dong Yanbo , Peng Peipei , Huang Fang , Wang Peng , Zhang Haoqian , Zhou Jianguang , Wang Youliang , Wei Bo , Shang Zeng-Fu , Li Shanhu
Published: January 2021

The PI3K/AKT/mTOR signaling pathway is constitutively active in PTEN-deficient cancer cells, and its targeted inhibition has significant anti-tumor effects. However, the efficacy of targeted therapies is often limited due to drug resistance. The relevant signaling pathways in PTEN-deficient cancer cells treated with the PI3K/mTOR inhibitor BEZ235 were screened using a phosphokinase array, and further validated following treatment with multiple PI3K/AKT/mTOR inhibitors or AKT knockdown. The correlation between PTEN expression levels and STAT3 kinase phosphorylation in the tissue microarrays of gastric cancer patients was analyzed by immunohistochemistry. Cell proliferation and clonogenic assays were performed on the suitably treated PTEN-deficient cancer cells. Cytokine arrays, small molecule inhibition and knockdown assays were performed to identify related factors. PTEN-deficient tumor xenografts were established in nude mice that were treated with PI3K/AKT/mTOR and/or STAT3 inhibitors. PTEN deficiency was positively correlated with low STAT3 activity. PI3K/mTOR inhibitors increased the expression and secretion of macrophage migration inhibitory factor (MIF) and activated the JAK1/STAT3 signaling pathway. Both cancer cells and in vivo tumor xenografts showed that the combined inhibition of PI3K/AKT/mTOR and STAT3 activity enhanced the inhibitory effect of BEZ235 on the proliferation of PTEN-deficient cancer cells. Our findings provide a scientific basis for a novel treatment strategy in cancer patients with PTEN deficiency.
PBK phosphorylates MSL1 to elicit epigenetic modulation of CD276 in nasopharyngeal carcinoma
Authors: Wang Meng-Yao , Qi Bin , Wang Fang , Lin Zhi-Rui , Li Ming-Yi , Yin Wen-Jing , Zhu Yan-Yi , He Lu , Yu Yi , Yang Fang , Liu Jin-Quan , Chen Dong-Ping
Published: January 2021

CD276 (also known as B7–H3, an immune checkpoint molecule) is aberrantly overexpressed in many cancers. However, the upregulation mechanism and in particular, whether oncogenic signaling has a role, is unclear. Here we demonstrate that a pro-oncogenic kinase PBK, the expression of which is associated with immune infiltration in nasopharyngeal carcinoma (NPC), stimulates the expression of CD276 epigenetically. Mechanistically, PBK phosphorylates MSL1 and enhances the interaction between MSL1 and MSL2, MSL3, and KAT8, the components of the MSL complex. As a consequence, PBK promotes the enrichment of MSL complex on CD276 promoter, leading to the increased histone H4 K16 acetylation and the activation of CD276 transcription. In addition, we show that CD276 is highly upregulated and associated with immune infiltrating levels in NPC. Collectively, our findings describe a novel PBK/MSL1/CD276 signaling axis, which may play an important role in immune evasion of NPC and may be targeted for cancer immunotherapy.
Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder
Authors: Nunes Abraham , Stone William , Ardau Raffaella , Berghöfer Anne , Bocchetta Alberto , Chillotti Caterina , Deiana Valeria , Degenhardt Franziska , Forstner Andreas J. , Garnham Julie S. , Grof Eva , Hajek Tomas , Manchia Mirko , Mattheisen Manuel , McMahon Francis , Müller-Oerlinghausen Bruno , Nöthen Markus M. , Pinna Marco , Pisanu Claudia , O’Donovan Claire , Rietschel Marcella D. C. , Rouleau Guy , Schulze Thomas , Severino Giovanni , Slaney Claire M. , Squassina Alessio , Suwalska Aleksandra , Turecki Gustavo , Uher Rudolf , Zvolsky Petr , Cervantes Pablo , del Zompo Maria , Grof Paul , Rybakowski Janusz , Tondo Leonardo , Trappenberg Thomas , Alda Martin
Published: January 2021

Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with “exemplary phenotypes”—those whose clinical features are reliably associated with LiR and non-response (LiNR)—are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a “clinical exemplar score,” which measures the degree to which a subject’s clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the “best clinical exemplars”) were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the “poor clinical exemplars”). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer’s amyloid–secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.
Multi-environment gene interactions linked to the interplay between polysubstance dependence and suicidality
Authors: Polimanti Renato , Levey Daniel F. , Pathak Gita A. , Wendt Frank R. , Nunez Yaira Z. , Ursano Robert J. , Kessler Ronald C. , Kranzler Henry R. , Stein Murray B. , Gelernter Joel
Published: January 2021

Substance dependence diagnoses (SDs) are important risk factors for suicidality. We investigated the associations of multiple SDs with different suicidality outcomes, testing how genetic background moderates these associations. The Yale-Penn cohort (N = 15,557) was recruited to investigate the genetics of SDs. The Army STARRS (Study to Assess Risk and Resilience in Servicemembers) cohort (N = 11,236) was recruited to evaluate mental health risk and resilience among Army personnel. We applied multivariate logistic regression to investigate the associations of SDs with suicidality and, in the Yale-Penn cohort, we used the structured linear mixed model (StructLMM) to study multivariate gene–environment interactions. In Yale-Penn, lifetime polysubstance dependence was strongly associated with lifetime suicidality: having five SDs showed an association with suicidality, from odds ratio (OR) = 6.77 (95% confidence interval, CI = 5.74–7.99) for suicidal ideation (SI) to OR = 3.61 (95% CI = 2.7–4.86) for suicide attempt (SA). In Army STARRS, having multiple substance use disorders for alcohol and/or drugs was associated with increased suicidality ranging from OR = 2.88 (95% CI = 2.6–3.19) for SI to OR = 3.92 (95% CI = 3.19–4.81) for SA. In Yale-Penn, we identified multivariate gene–environment interactions (Bayes factors, BF > 0) of SI with respect to a gene cluster on chromosome 16 (LCAT, p = 1.82 × 10–7; TSNAXIP1, p = 2.13 × 10−7; CENPT, p = 2.32 × 10−7; PARD6A, p = 5.57 × 10−7) for opioid dependence (BF = 12.2), cocaine dependence (BF = 12.1), nicotine dependence (BF = 9.2), and polysubstance dependence (BF = 2.1). Comorbidity of multiple SDs is a significant associated with suicidality and heritability of suicidality is partially moderated by multivariate gene interactions.
Osteoclast-derived apoptotic bodies couple bone resorption and formation in bone remodeling
Authors: Ma Qinyu , Liang Mengmeng , Wu Yutong , Luo Fei , Ma Zaisong , Dong Shiwu , Xu Jianzhong , Dou Ce
Published: January 2021

Bone remodeling is precisely coordinated by bone resorption and formation. Apoptotic osteoclasts generate large amounts of apoptotic bodies (ABs) marking the end of the bone resorption phase, whereas the functions of osteoclast-derived ABs remain largely unknown. Here, we identified the molecular profile of ABs derived from osteoclasts at distinct differentiation stages and investigated their corresponding functions. ABs were isolated from apoptotic bone marrow macrophages, preosteoclasts, and mature osteoclasts induced by staurosporine. Proteomic signature analysis with liquid chromatography-tandem mass spectrometry suggested marked protein cargo differences among the different ABs. Further bioinformatic analysis showed that the proteomic signatures of the ABs were highly similar to those of their parental cells. Functionally, pOC-ABs induced endothelial progenitor cell differentiation and increased CD31hiEmcnhi endothelial cell formation in a murine bone defect model via their PDGF-BB cargo. mOC-ABs induced osteogenic differentiation of mesenchymal stem cells and facilitated osteogenesis via RANKL reverse signaling. In summary, we mapped the detailed proteomic landscapes of ABs derived from osteoclasts and showed that their potential biological roles are important in coupling bone formation with resorption during bone remodeling.
LncRNA linc00312 suppresses radiotherapy resistance by targeting DNA-PKcs and impairing DNA damage repair in nasopharyngeal carcinoma
Authors: Guo Zhen , Wang You-Hong , Xu Heng , Yuan Chun-Su , Zhou Hong-Hao , Huang Wei-Hua , Wang Hui , Zhang Wei
Published: January 2021

Radioresistance is the main obstacle in the clinical management of nasopharyngeal carcinoma (NPC). linc00312 is deregulated in a number of human cancers, including NPC. However, the detailed functions and underlying mechanisms of linc00312 in regulating radiosensitivity of NPC remains unknown. In this study, cox regression analysis was used to assess the association between linc00312 and NPC patients’ survival after radiotherapy. Our results reveal that linc00312 is significantly down-regulated in NPC tissues and patients with higher expression of linc00312 are significantly associated with longer overall survival and better short-term radiotherapy efficacy. Overexpression of linc00312 could increase the sensitivity of NPC cells to ionizing radiation, as indicated by clonogenic survival assay, comet assay, and flow cytometry. Mechanistically, RNA pull down and RNA immunoprecipitation were performed to investigate the binding proteins of linc00312. linc00312 directly binds to DNA-PKcs, hinders the recruitment of DNA-PKcs to Ku80, and inhibits phosphorylation of AKT–DNA–PKcs axis, therefore inhibiting the DNA damage signal sensation and transduction in the NHEJ repair pathway. In addition, linc00312 impairs DNA repair and cell cycle control by suppressing MRN–ATM–CHK2 signal and ATR–CHK1 signal. In summary, we identified DNA-PKcs as the binding protein of linc00312 and revealed a novel mechanism of linc00312 in the DNA damage response, providing evidence for a potential therapeutic strategy in NPC.
The HIV protease inhibitor Saquinavir attenuates sepsis-induced acute lung injury and promotes M2 macrophage polarization via targeting matrix metalloproteinase-9
Authors: Tong Yao , Yu Zhuang , Chen Zhixia , Zhang Renlingzi , Ding Xibing , Yang Xiaohu , Niu Xiaoyin , Li Mengzhu , Zhang Lingling , Billiar Timothy R. , Pitt Bruce R. , Li Quan
Published: January 2021

Imbalance of macrophage polarization plays an indispensable role in acute lung injury (ALI), which is considered as a promising target. Matrix metalloproteinase-9 (MMP-9) is expressed in the macrophage, and has a pivotal role in secreting inflammatory cytokines. We reported that saquinavir (SQV), a first-generation human immunodeficiency virus-protease inhibitor, restricted exaggerated inflammatory response. However, whether MMP-9 could regulate macrophage polarization and inhibit by SQV is still unknown. We focused on the important role of macrophage polarization in CLP (cecal ligation puncture)-mediated ALI and determined the ability of SQV to maintain M2 over M1 phenotype partially through the inhibition of MMP-9. We also performed a limited clinical study to determine if MMP-9 is a biomarker of sepsis. Lipopolysaccharide (LPS) increased MMP-9 expression and recombinant MMP-9 (rMMP-9) exacerbated LPS-mediated M1 switching. Small interfering RNA to MMP-9 inhibited LPS-mediated M1 phenotype and SQV inhibition of this switching was reversed with rMMP-9, suggesting an important role for MMP-9 in mediating LPS-induced M1 phenotype. MMP-9 messenger RNA levels in peripheral blood mononuclear cells of these 14 patients correlated with their clinical assessment. There was a significant dose-dependent decrease in mortality and ALI after CLP with SQV. SQV significantly inhibited LPS-mediated M1 phenotype and increased M2 phenotype in cultured RAW 264.7 and primary murine bone marrow-derived macrophages as well as lung macrophages from CLP-treated mice. This study supports an important role for MMP-9 in macrophage phenotypic switching and suggests that SQV-mediated inhibition of MMP-9 may be involved in suppressing ALI during systemic sepsis.
Mtu1 defects are correlated with reduced osteogenic differentiation
Authors: He Qiufen , Zhao Qiong , Li Qianqian , Pan Ruolang , Li Xiongfeng , Chen Ye
Published: January 2021

Accumulating evidence has revealed that mitochondria dynamics and function regulation is essential for the successful mesenchymal stem cell (MSC) differentiation. In the present study, the researchers reported for the first time that Mtu1 defects are correlated with reduced osteogenic differentiation. Using in vitro cultured bone marrow MSCs and stromal cell line MS5, we demonstrated that depressed Mtu1 expression was associated with reduced 2-thiouridine modification of the U34 of mitochondrial tRNAGln, tRNAGlu, and tRNALys, which led to respiratory deficiencies and reduced mitochondrial ATP production, and finally suppressed osteogenic differentiation. As expected, these Mtu1-deficient mice exhibited obvious osteopenia. Therefore, our findings in this study provide new insights into the pathophysiology of osteopenia.
SP1-induced long non-coding RNA SNHG6 facilitates the carcinogenesis of chondrosarcoma through inhibiting KLF6 by recruiting EZH2
Authors: Pu Fei-Fei , Shi De-Yao , Chen Ting , Liu Yu-Xuan , Zhong Bin-Long , Zhang Zhi-Cai , Liu Wei-Jian , Wu Qiang , Wang Bai-Chuan , Shao Zeng-Wu , He Tong-Chuan , Liu Jian-Xiang
Published: January 2021

Small nucleolar RNA host gene 6 (SNHG6) is a newly discovered long non-coding RNA (lncRNA), while the regulatory mechanism of SNHG6 in chondrosarcoma is largely unknown. Here we found that SNHG6 expression was upregulated and showed positive correlation with the progression of chondrosarcoma. Functional assays demonstrated that SNHG6 was required for the proliferation, migration, and invasion of chondrosarcoma cells. Mechanistic study revealed that SNHG6 could recruit EZH2 and maintain high level of H3K27me3 to repress the transcription of tumor-suppressor genes, including KLF6. KLF6 was found to bind to the promoter region of SP1 and restrained its transcription, while SP1 could be recruited to the promoter region of SNHG6 and promoted its transcription to form a positive loop. In summary, this study reveals that SP1-induced SNHG6 forms a positive loop to facilitate the carcinogenesis of chondrosarcoma through the suppression of KLF6 by recruiting EZH2, which manifests the oncogenic function of SNHG6 in chondrosarcoma.
Necroptosis is active and contributes to intestinal injury in a piglet model with lipopolysaccharide challenge
Authors: Liu Yulan , Xu Qiao , Wang Yang , Liang Tianzeng , Li Xiangen , Wang Dan , Wang Xiuying , Zhu Huiling , Xiao Kan
Published: January 2021

Necroptosis, a newly discovered form of programmed cell death that combines the features of apoptosis and necrosis, is important in various physiological and pathological disorders. However, the role of necroptosis on intestinal injury during sepsis has been rarely evaluated. This study aimed to investigate the presence of necroptosis in intestinal injury, and its contribution to intestinal injury in a piglet model challenged with Escherichia coli lipopolysaccharide (LPS). Firstly, a typical cell necrotic phenomenon was observed in jejunum of LPS-challenged pigs by transmission electron microscope. Protein expression of necroptosis signals including receptor-interacting protein kinase (RIP) 1, RIP3, and phosphorylated mixed-lineage kinase domain-like protein (MLKL), mitochondrial proteins including phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (DRP1), and cytoplasmic high-mobility group box 1 (HMGB1) were time-independently increased in jejunum of LPS-challenged piglets, which was accompanied by the impairment of jejunal morphology, and digestive and barrier function indicated by lower activities of jejunal disaccharidases and protein expression of jejunal tight junction proteins claudin-1 and occludin. Pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 were also dynamically induced in serum and jejunum of piglets after LPS challenge. Moreover, pretreatment with necrostatin-1 (Nec-1), an specific inhibitor of necroptosis, inhibited necroptosis indicated by decreased necrotic ultrastructural changes and decreased protein expression of RIP1, RIP3, and phosphorylated MLKL as well as PGAM5, DRP1, and cytoplasmic HMGB1. Nec-1 pretreatment reduced jejunal morphological injury, and improved digestive and barrier function. Nec-1 pretreatment also decreased the levels of serum and jejunal pro-inflammatory cytokines and the numbers of jejunal macrophages and monocytes. These findings indicate for the first time that necroptosis is present and contributes to LPS-induced intestinal injury. Nec-1 may have a preventive effect on intestinal injury during sepsis.
CHIP promotes Wnt signaling and regulates Arc stability by recruiting and polyubiquitinating LEF1 or Arc
Authors: Liu Yuchun , Sun Yao , Huang Yonghui , Cheng Kang , Xu Yuming , Tian Qingnan , Zhang Shoutao
Published: January 2021

The carboxyl terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase, participates in many cellular processes such as protein degradation, trafficking, autophagy, apoptosis, and multiple signaling transductions. The mutant of CHIP (p.T246M) causes the spinocerebellar autosomal recessive 16 (SCAR16), a neurodegenerative disease characterized by spinocerebellar atrophy. Previous studies have shown that Wnt signaling and activity-regulated cytoskeleton-associated protein (Arc) play important roles in neurodegenerative diseases. However, the mechanisms by which CHIP regulates Wnt signaling and the stability of Arc that may affect SCAR16 are still unclear. We show that overexpression of CHIP promoted the activation of Wnt signaling, and enhanced the interaction between LEF1 and β-catenin through heightening the K63-linked polyubiquitin chains attached to LEF1, while the knockdown of CHIP had the opposite effect. Moreover, we verified that Wnt signaling was inhibited in the rat models of SCAR16 induced by the CHIP (p.T246M) mutant. CHIP also accelerated the degradation of Arc and regulated the interaction between Arc and GSK3β by heightening the K48- or K63-linked polyubiquitin chains, which further potentiated the interaction between GSK3β and β-catenin. Our data identify that CHIP is an undescribed regulator of Wnt signaling and Arc stability which may be related to the occurrence of SCAR16.
Mutual dependency between lncRNA LETN and protein NPM1 in controlling the nucleolar structure and functions sustaining cell proliferation
Authors: Wang Xianteng , Hu Xiaolin , Song Wanlu , Xu Hui , Xiao Zhengtao , Huang Rongyao , Bai Qingran , Zhang Fan , Chen Yongzhen , Liu Yu , Fang Jianhuo , Li Xin , Shen Qin , Zhao Haitao , Yang Xuerui
Published: January 2021

Fundamental processes such as ribosomal RNA synthesis and chromatin remodeling take place in the nucleolus, which is hyperactive in fast-proliferating cells. The sophisticated regulatory mechanism underlying the dynamic nucleolar structure and functions is yet to be fully explored. The present study uncovers the mutual functional dependency between a previously uncharacterized human long non-coding RNA, which we renamed LETN, and a key nucleolar protein, NPM1. Specifically, being upregulated in multiple types of cancer, LETN resides in the nucleolus via direct binding with NPM1. LETN plays a critical role in facilitating the formation of NPM1 pentamers, which are essential building blocks of the nucleolar granular component and control the nucleolar functions. Repression of LETN or NPM1 led to similar and profound changes of the nucleolar morphology and arrest of the nucleolar functions, which led to proliferation inhibition of human cancer cells and neural progenitor cells. Interestingly, this inter-dependency between LETN and NPM1 is associated with the evolutionarily new variations of NPM1 and the coincidental emergence of LETN in higher primates. We propose that this human-specific protein–lncRNA axis renders an additional yet critical layer of regulation with high physiological relevance in both cancerous and normal developmental processes that require hyperactive nucleoli.
Satb2 neurons in the parabrachial nucleus mediate taste perception
Authors: Jarvie Brooke C. , Chen Jane Y. , King Hunter O. , Palmiter Richard D.
Published: January 2021

The neural circuitry mediating taste has been mapped out from the periphery to the cortex, but genetic identity of taste-responsive neurons has remained elusive. Here, we describe a population of neurons in the gustatory region of the parabrachial nucleus that express the transcription factor Satb2 and project to taste-associated regions, including the gustatory thalamus and insular cortex. Using calcium imaging in awake, freely licking mice, we show that Satb2 neurons respond to the five basic taste modalities. Optogenetic activation of these neurons enhances taste preferences, whereas chronic inactivation decreases the magnitude of taste preferences in both brief- and long-access taste tests. Simultaneous inactivation of Satb2 and calcitonin gene-related peptide neurons in the PBN abolishes responses to aversive tastes. These data suggest that taste information in the parabrachial nucleus is conveyed by multiple populations of neurons, including both Satb2 and calcitonin gene-related peptide neurons.
Perineuronal nets stabilize the grid cell network
Authors: Christensen Ane Charlotte , Lensjø Kristian Kinden , Lepperød Mikkel Elle , Dragly Svenn-Arne , Sutterud Halvard , Blackstad Jan Sigurd , Fyhn Marianne , Hafting Torkel
Published: January 2021

Grid cells are part of a widespread network which supports navigation and spatial memory. Stable grid patterns appear late in development, in concert with extracellular matrix aggregates termed perineuronal nets (PNNs) that condense around inhibitory neurons. It has been suggested that PNNs stabilize synaptic connections and long-term memories, but their role in the grid cell network remains elusive. We show that removal of PNNs leads to lower inhibitory spiking activity, and reduces grid cells’ ability to create stable representations of a novel environment. Furthermore, in animals with disrupted PNNs, exposure to a novel arena corrupted the spatiotemporal relationships within grid cell modules, and the stored representations of a familiar arena. Finally, we show that PNN removal in entorhinal cortex distorted spatial representations in downstream hippocampal neurons. Together this work suggests that PNNs provide a key stabilizing element for the grid cell network.
Synthesis of arylamines and N-heterocycles by direct catalytic nitrogenation using N2
Authors: Wang Kai , Deng Zi-Hao , Xie Si-Jun , Zhai Dan-Dan , Fang Hua-Yi , Shi Zhang-Jie
Published: January 2021

Ammonia and nitric acid are two key platform chemicals to introduce nitrogen atoms into organic molecules in chemical industry. Indeed, nitric acid is mostly produced through the oxidation of ammonia. The ideal nitrogenation would involve direct use of dinitrogen (N2) as a N source to construct N-containing organic molecules. Herein, we report an example of direct catalytic nitrogenation to afford valuable diarylamines, triarylamines, and N-heterocycles from easily available organohalides using dinitrogen (N2) as the nitrogen source in a one-pot/two-step protocol. With this method, 15N atoms are easily incorporated into organic molecules. Structurally diversified polyanilines are also generated in one pot, showing great potential for materials chemistry. In this protocol, lithium nitride, generated in situ with the use of lithium as a reductant, is confirmed as a key intermediate. This chemistry provides an alternative pathway for catalytic nitrogenation to synthesize highly valuable N-containing chemicals from dinitrogen.
Single ion qubit with estimated coherence time exceeding one hour
Authors: Wang Pengfei , Luan Chun-Yang , Qiao Mu , Um Mark , Zhang Junhua , Wang Ye , Yuan Xiao , Gu Mile , Zhang Jingning , Kim Kihwan
Published: January 2021

Realizing a long coherence time quantum memory is a major challenge of current quantum technology. Until now, the longest coherence-time of a single qubit was reported as 660 s in a single 171Yb+ ion-qubit through the technical developments of sympathetic cooling and dynamical decoupling pulses, which addressed heating-induced detection inefficiency and magnetic field fluctuations. However, it was not clear what prohibited further enhancement. Here, we identify and suppress the limiting factors, which are the remaining magnetic-field fluctuations, frequency instability and leakage of the microwave reference-oscillator. Then, we observe the coherence time of around 5500 s for the 171Yb+ ion-qubit, which is the time constant of the exponential decay fit from the measurements up to 960 s. We also systematically study the decoherence process of the quantum memory by using quantum process tomography and analyze the results by applying recently developed resource theories of quantum memory and coherence. Our experimental demonstration will accelerate practical applications of quantum memories for various quantum information processing, especially in the noisy-intermediate-scale quantum regime.
Stable, high-performance, dendrite-free, seawater-based aqueous batteries
Authors: Tian Huajun , Li Zhao , Feng Guangxia , Yang Zhenzhong , Fox David , Wang Maoyu , Zhou Hua , Zhai Lei , Kushima Akihiro , Du Yingge , Feng Zhenxing , Shan Xiaonan , Yang Yang
Published: January 2021

Metal anode instability, including dendrite growth, metal corrosion, and hetero-ions interference, occurring at the electrolyte/electrode interface of aqueous batteries, are among the most critical issues hindering their widespread use in energy storage. Herein, a universal strategy is proposed to overcome the anode instability issues by rationally designing alloyed materials, using Zn-M alloys as model systems (M = Mn and other transition metals). An in-situ optical visualization coupled with finite element analysis is utilized to mimic actual electrochemical environments analogous to the actual aqueous batteries and analyze the complex electrochemical behaviors. The Zn-Mn alloy anodes achieved stability over thousands of cycles even under harsh electrochemical conditions, including testing in seawater-based aqueous electrolytes and using a high current density of 80 mA cm−2. The proposed design strategy and the in-situ visualization protocol for the observation of dendrite growth set up a new milestone in developing durable electrodes for aqueous batteries and beyond.
NOD2 deficiency increases retrograde transport of secretory IgA complexes in Crohn’s disease
Authors: Rochereau Nicolas , Roblin Xavier , Michaud Eva , Gayet Rémi , Chanut Blandine , Jospin Fabienne , Corthésy Blaise , Paul Stéphane
Published: January 2021

Intestinal microfold cells are the primary pathway for translocation of secretory IgA (SIgA)-pathogen complexes to gut-associated lymphoid tissue. Uptake of SIgA/commensals complexes is important for priming adaptive immunity in the mucosa. This study aims to explore the effect of SIgA retrograde transport of immune complexes in Crohn’s disease (CD). Here we report a significant increase of SIgA transport in CD patients with NOD2-mutation compared to CD patients withoutNOD2mutation and/or healthy individuals. NOD2 has an effect in the IgA transport through human and mouse M cells by downregulating Dectin-1 and Siglec-5 expression, two receptors involved in retrograde transport. These findings define a mechanism of NOD2-mediated regulation of mucosal responses to intestinal microbiota, which is involved in CD intestinal inflammation and dysbiosis.
Highly explosive basaltic eruptions driven by CO2 exsolution
Authors: Allison Chelsea M. , Roggensack Kurt , Clarke Amanda B.
Published: January 2021

The most explosive basaltic scoria cone eruption yet documented (>20 km high plumes) occurred at Sunset Crater (Arizona) ca. 1085 AD by undetermined eruptive mechanisms. We present melt inclusion analysis, including bubble contents by Raman spectroscopy, yielding high total CO2 (approaching 6000 ppm) and S (~2000 ppm) with moderate H2O (~1.25 wt%). Two groups of melt inclusions are evident, classified by bubble vol%. Modeling of post-entrapment modification indicates that the group with larger bubbles formed as a result of heterogeneous entrapment of melt and exsolved CO2 and provides evidence for an exsolved CO2 phase at magma storage depths of ~15 km. We argue that this exsolved CO2 phase played a critical role in driving this explosive eruption, possibly analogous to H2O exsolution driving silicic caldera-forming eruptions. Because of their distinct gas compositions relative to silicic magmas (high S and CO2), even modest volume explosive basaltic eruptions could impact the atmosphere.