bluuebunny/crossref_metadata_2025 huggingface dataset:
159 Safety and Efficacy of Lurasidone in Children and Adolescents with Bipolar Depression: Results from a 2-Year Open-label Extension Study
Authors: DelBello Melissa P. , Goldman Robert , Tocco Michael , Deng Ling , Pikalov Andrei
Published: April 2020

Background:

Bipolar I disorder frequently has an early onset, with an estimated prevalence rate of 1.8% in pediatric populations. Early onset is associated with a high degree of chronicity; however, limited data are available on the long-term efficacy of drug therapies in pediatric populations. The aim of the current study was to evaluate the long-term safety and efficacy of lurasidone in children and adolescents with bipolar depression.

Method:

Patients 10-17 years with bipolar I depression were randomized to 6 weeks of double-blind (DB) treatment with lurasidone or placebo. Patients who completed the study were eligible to enroll in a 2-year, open-label (OL) extension study in which patients were continued on flexibly-dosed lurasidone (20-80 mg/d; LUR-LUR) or switched from placebo to lurasidone (PBO-LUR). The primary efficacy measure was the Children’s Depression Rating Scale, Revised (CDRS-R); response was defined as ≥50% reduction from DB baseline in the CDRS-R total score.

Results:

A total of 306 patients completed the 6-week DB study and entered the extension study; 195 (63.7%) completed 52 weeks, and 168 (54.9%) completed 104 weeks of treatment. Mean CDRS-R total score at DB baseline was 59.4 in patients treated with lurasidone, and 58.7 in patients treated with placebo; and mean CDRS-R total score at OL baseline (after 6 weeks of DB treatment) was 36.6 in the LUR-LUR group and 41.9 in the PBO-LUR group. For the total sample of patients in the OL study, mean change (from OL baseline) in the CDRS-R score was -13.4 at week 52 and -16.4 at week 104; and responder rates were 51.0% at OL baseline (64.5% for LUR-LUR; 36.9% for PBO-LUR), 88.4% at week 52, and 91.1% at week 104. During OL treatment with lurasidone, 31 patients (10.1%) discontinued due to an adverse event. The most commonly reported events were headache (23.9%), nausea (16.4%), and somnolence (9.8%). OL treatment with lurasidone was associated with few effects on metabolic parameters or prolactin. Mean change from DB baseline in weight was +4.25 kg at week 52 (vs. an expected weight gain of 3.76 kg based on CDC normative data), and +6.75 kg at week 104 (vs. CDC expected weight gain of 6.67 kg).

Conclusion:

Two years of treatment with lurasidone in children and adolescents with bipolar depression was generally well-tolerated, with relatively low rates of study discontinuation. Lurasidone treatment was associated with few effects on weight, metabolic parameters, and prolactin. Patients also continued to experience improvement in depressive symptoms during long-term treatment with lurasidone.

Clinicaltrials.gov identifier: NCT01914393

Funding Acknowledgements:

Supported by funding from Sunovion Pharmaceuticals Inc.
172 A Phase 3, Multicenter Study to Assess the Long-Term Safety, Tolerability, and Efficacy of Olanzapine/Samidorphan in Patients with Schizophrenia
Authors: Yagoda Sergey , Graham Christine , Simmons Adam , Arevalo Christina , Cheng Yansong , McDonnell David
Published: April 2020

Background: ALKS 3831, a combination of olanzapine and samidorphan (OLZ/SAM), is in development for the treatment of schizophrenia and is intended to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. We report the safety, tolerability, and efficacy of OLZ/SAM in patients with schizophrenia in a phase 3, 52-week, open-label extension study.

Methods:

Patients aged 18–70 years who completed a previous phase 3, 4-week, inpatient acute efficacy study were switched from OLZ/SAM, olanzapine, or placebo to OLZ/SAM. Study assessments included adverse events (AEs), weight, clinical laboratory testing, and Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S) scores.

Results:

281 patients were enrolled; 277 (mean age, 41.4 years) received ≥1 dose of study drug, and 183 (66.1%) completed the extension study. The most common reasons for discontinuation were withdrawal by patient (15.5%), loss to follow-up (6.9%), and AEs (5.8%). AEs were reported in 136 (49.1%) patients; most were mild in severity. The most common AEs were increased weight (13.4%), somnolence (8.3%), nasopharyngitis (4.0%), and headache (4.0%). Mean weight increase from baseline in patients completing 52 weeks of treatment was 1.86 kg, a 2.79% increase. No clinically significant changes in mean laboratory parameters were observed. Mean (SD) changes from baseline to week 52 in PANSS total score and CGI-S score were –16.2 (15.41) and –0.9 (0.92), respectively (both P<0.001).

Discussion:

OLZ/SAM was generally well tolerated with a safety profile that supports long-term treatment. During this 52-week extension study, there were improvements in schizophrenia symptoms.

Funding Acknowledgements:

This study was funded by Alkermes, Inc.
183 Antidepressant Adherence and Alternative Future Options in Pacific Islander Youth
Authors: Portman Will , Wang Dawei , Ruege Andrew
Published: April 2020

Objectives:

To investigate the current response to psychopharmacology and transcranial magnetic stimulation (TMS) in Pacific Islander adolescents with Major Depressive Disorder (MDD).

BACKGROUND:

40-60% of youth with Major Depressive Disorder (MDD) have a limited response to current treatment protocols and require either (a) medications with a wider side effect profile, (b) intensive psychosocial programs that interfere with school, and/or (c) publicly spurned options (electroconvulsive therapy). Such results are tempered further when working with Pacific Islanders, as such youth and families have shown in multiple studies. The aversion to such standard treatment is concerning, as Native Hawaiian adolescents have a higher risk of suicide than other adolescents in Hawaii (12.9/100,000 youth per year). With this in mind, the investigators wondered how a novel, non-pharmacological approach to depression treatment in children, transcranial magnetic stimulation (TMS), would fair.

METHODS:

2 literature searches (utilizing Pubmed, Ovid, Google Scholar, and OneSearch) were conducted on 6/10/19: 1 investigating rTMS in adolescent depression, the other researching rTMS in depression in Native Hawaiian or other Pacific Islander youth.

RESULTS:

At this point in time, 10 studies exist testing TMS’ effects in children and adolescents with treatment refractory depression. 9 of said studies were open-label trials; 1 was a small (n=2) RCT (with both patients randomized to the active arm). Of those evaluating depression severity through Children’s Depression Rating Scale-revised (“CDRS-R”) scores, 100% of the trials (8/8) displayed a statistically significant improvement. None of the trials of the 1st series of searches nor the entirety of the 2nd series yielded information as to how TMS fairs in Native Hawaiian or other Pacific Islander youth.

CONCLUSIONS:

No studies exist that can verify the efficacy of TMS in youth, of Oceanic origin or otherwise, with the same degree of scrutiny as currently done in adults. Therefore, our group is engaging in a pilot study to evaluate the performance of TMS for the treatment of MDD in Native Hawaiian and other Pacific Islander adolescents aged 12-17; we are planning on then progressing on to a sham-controlled RCT in a larger sample size of the same population to test its efficacy in not just Pacific Islanders, but all youth.

Funding Acknowledgements:

no funding
184 Insulin Sensitivity and Glucose Metabolism of Olanzapine and Combination Olanzapine and Samidorphan: A Phase 1 Exploratory Study in Healthy Volunteers
Authors: Martin William , Graham Christine , Morrow Linda , Beysen Carine , Toledo Frederico G.S. , Bajorunas Daiva , Jiang Ying , Silverman Bernard , McDonnell David , Namchuk Mark N. , Newcomer John W.
Published: April 2020

Background:

A combination of olanzapine and samidorphan (OLZ/SAM) is in development for schizophrenia to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. The objective of this phase 1 exploratory study was to assess metabolic treatment effects of OLZ/SAM.

Methods:

Healthy, non-obese adults (18–40 years) were randomized 2:2:1 to once-daily OLZ/SAM, olanzapine, or placebo for 21 days. Assessments included oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, weight gain, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance.

Results:

Sixty subjects were randomized (OLZ/SAM, n=24; olanzapine, n=24; placebo, n=12); 19 (79.2%), 22 (91.7%), and 11 (91.7%), respectively, completed the study. In the OGTT, olanzapine led to significant hyperinsulinemia (P<0.0001) and significantly reduced insulin sensitivity (2-hour Matsuda index) at day 19 vs baseline (P=0.0012), changes not observed with OLZ/SAM. No significant between-group differences were observed for change from baseline in clamp-derived insulin sensitivity index at day 21. Least squares mean weight change from baseline was similar with OLZ/SAM (3.16 kg) and olanzapine (2.87 kg); both were significantly higher than placebo (0.57 kg; both P<0.01). Caloric intake significantly decreased from baseline to day 22 with OLZ/SAM (P=0.015) but not with olanzapine or placebo. Forty-nine subjects (81.7%) experienced ≥1 AE (OLZ/SAM, 87.5%; olanzapine, 79.2%; placebo, 75.0%).

Conclusions:

In this exploratory study, hyperinsulinemia and decreased insulin sensitivity were observed in the OGTT with olanzapine but not with OLZ/SAM or placebo. Clamp-derived insulin sensitivity index and weight changes were similar with OLZ/SAM and olanzapine in healthy subjects during the 3-week study.

Funding Acknowledgements:

This study was funded by Alkermes, Inc.
192 Eye’ve Seen Enough: Oculogyric Crisis in a 13 year old Male Treated for Comorbid ADHD and Psychosis After Stopping Lisdexamphetamine
Authors: Myers Capt Kathryn , Kallinicos Robert , Lucas Christopher
Published: April 2020

Title:

Eye’ve Seen Enough: Oculogyric Crisis in a 13 year old Male Treated for Comorbid ADHD and Psychosis After Stopping Lisdexamphetamine

Background:

Oculogyric crisis is a dystonic movement disorder caused by sustained contractions of ocular muscles that may last minutes to hours. It is known to occur during hypodopaminergic states. Combined use of stimulants and antipsychotics increase the risk for developing a hypodopaminergic state in the brain leading to various dystonic reactions described as a stimulant-antipsychotic syndrome (SAS).

Case:

A unique example of SAS occurred in a 13 year-old male with comorbid ADHD and schizoaffective disorder hospitalized for acute psychotic decompensation who had been treated for several months with risperidone and lisdexamphetamine. On admission, the patient had received olanzapine 5mg ODT for acute agitation and lisdexamphetamine was discontinued. He started to cross-taper from risperidone to quetiapine. In this setting he developed dystonia including an oculogyric crisis that resolved with diphenhydramine.

Conclusions:

In this case the use of lisdexamphetamine and risperidone may have set up an environment where there was decreased endogenously made dopamine and up-regulation of postsynaptic dopamine receptors. Upon discontinuation of the lisdexamphetamine and acute use of additional atypical antipsychotics (olanzapine and quetiapine), the body experienced a hypodopaminergic state resulting in dystonic reactions that included an oculogyric crisis. This case is unique from previously reported cases by occurring with the use and discontinuation of lisdexamphetamine while most reported cases involved a derivative of methylphenidate as the stimulant. This report adds to the literature showing the importance of monitoring and being aware of potential medication interactions especially when treating for comorbid conditions. This is even more important to recognize after adding or removing either of these medications.

Funding: no funding.
Paul Williams: The Cage Mix
Authors: DAVENPORT MARK
Published: April 2020

Demystifying a largely misunderstood chapter in John Cage's biographical narrative, this article explores the pivotal role architect and philanthropist Paul Williams played in Cage's life, and for whom Cage named his famous magnetic tape composition Williams Mix (1952–53). Retracing the activities of both men, beginning with their earliest encounter at the experimental Black Mountain College in North Carolina in 1948, this investigation documents for the first time the extent of their mutually devoted relationship. Newly uncovered source material and photographs also reveal the valuable contributions Williams made as primary benefactor and mastermind of the intentional community called the Gatehill Cooperative (a.k.a. “Stony Point”), a place Cage called home for seventeen years (1954–71). There Cage developed a “hunger for nature,” wrote his widely read and influential book Silence (1961), and undertook some of his most significant musical projects.
Achieving sustainability requires systemic business transformation
Authors: Waddock Sandra
Published: April 2020

Non-technical summary

Achieving sustainability requires that businesses transform; however, it is virtually impossible in today's competitive environment for individual businesses to do what is needed to bring about systemic transformation. Instead, it is the context around businesses, including the public policy environment and changes by major actors, which must shift so that the pressures, constraints and demands on businesses can epimimetically drive their competitive instincts in the direction of wellbeing for all.
Horse purslane (Trianthema portulacastrum) control in pigeonpea with PRE and POST herbicides
Authors: Mahajan Gulshan , Rachaputi R. C. N. , Chauhan Bhagirath Singh
Published: April 2020

Pigeonpea has great potential as a profitable summer legume rotational crop in cereal farming systems of subtropical Australia. Pigeonpea requires season-long weed control, but options for controlling broadleaf weeds in pigeonpea with POST herbicides are limited. The objective of this study was to evaluate the performance of different herbicides (PRE: pendimethalin; POST: acifluorfen, bentazon, and imazapic) applied singly or in sequence for horse purslane control in pigeonpea and their impact on pigeonpea yield. Field experiments were conducted in 2017 and 2018 at Gatton, Australia. Pendimethalin applied PRE at 1.14 kg ai ha−1 reduced horse purslane biomass by 87% and 92% and produced 32% and 105% higher grain yield compared with the nontreated control in 2017 and 2018, respectively. Imazapic applied POST at 0.10 kg ai ha−1 reduced horse purslane biomass by 79% and 82% and increased grain yield by 60% and 88% compared with the nontreated control in 2017 and 2018, respectively. Acifluorfen applied POST (0.34 and 0.42 kg ai ha−1) caused 16% to 48% injury to pigeonpea at 45 d after treatment. Control of horse purslane ranged from 87% to 92% (biomass reduction) with pendimethalin applied PRE at 1.14 kg ai ha−1 and was comparable with pendimethalin applied PRE at 0.91 kg ai ha−1 in the sequential application, and imazapic at 0.08 kg ai ha−1 or bentazon at 0.96 kg ai ha−1. The study findings suggest if farmers miss the PRE application of pendimethalin or are unable to achieve season-long weed control, POST application of imazapic is an alternate. This research provided herbicide options for control of horse purslane in pigeonpea that could be used in rotations for reducing the selection pressure of weeds.
Spatiotemporal Seismic Structure Variations Associated With the 2018 Kīlauea Eruption Based on Temporary Dense Geophone Arrays
Authors: Wu Sin‐Mei , Lin Fan‐Chi , Farrell Jamie , Shiro Brian , Karlstrom Leif , Okubo Paul , Koper Keith
Published: April 2020

During the 2018 Kīlauea volcanic eruption, lava erupted from a series of new fissures in the lower East Rift Zone more than 30 km away from the summit through a dike intrusion. Between late May and early August, variations in the effusion rate at the persistent eruptive vent (Fissure 8) were observed following near‐daily summit caldera collapse events. Targeting the ongoing eruptive activity and the subsurface magma movement, we deployed a temporary dense seismic array. The observed time‐lapse changes in seismic velocity associated with the response of the summit collapse in three areas are presented in this study. The results show (1) clear spatially dependent co‐collapse velocity reductions across the newly‐intruded dike structure, (2) a gradual post‐collapse velocity increase near Fissure 8 correlated with the surge of magma supply, and (3) a gradual post‐collapse velocity increase on the summit likely associated with reservoir pressurization and crustal welding.
Optimization of Deep Learning Precipitation Models Using Categorical Binary Metrics
Authors: Larraondo Pablo R. , Renzullo Luigi J. , Van Dijk Albert I. J. M. , Inza Inaki , Lozano Jose A.
Published: April 2020

This work introduces a methodology for optimizing neural network models using a combination of continuous and categorical binary indices in the context of precipitation forecasting. Probability of detection and false alarm rate are popular metrics used in the verification of precipitation models. However, machine learning models trained using gradient descent cannot be optimized based on these metrics, as they are not differentiable. We propose an alternative formulation for these categorical indices that are differentiable and we demonstrate how they can be used to optimize the skill of precipitation neural network models defined as a multiobjective optimization problem. To our knowledge, this is the first proposal of a methodology for optimizing weather neural network models based on categorical indices.
Predicting the Future of Greenland’s Melting Ice Sheet
Authors: Stanley Sarah
Published: April 2020

Despite recent leaps in our understanding of how climate change is affecting Greenland’s glaciers, many uncertainties remain.
Oktoberfest’s Methane Rise Is the Wurst
Authors: Kornei Katherine
Published: April 2020

Incomplete combustion and biogenic emissions—exhalations and flatulence—make Oktoberfest a significant, albeit temporary, source of the potent greenhouse gas.
Chronic inhibition of GABA synthesis in the infralimbic cortex facilitates conditioned safety memory and reduces contextual fear
Authors: Kreutzmann Judith C. , Fendt Markus
Published: April 2020

Accurate discrimination between danger and safety cues is essential for survival. Recent findings in humans indicate that patients suffering from anxiety disorders cannot reliably use safety cues in order to inhibit fear responses. However, the neuroanatomical pathways of conditioned safety are still unclear. Aim of the present study was to investigate whether chronic inhibition of GABA synthesis in the infralimbic (IL) cortex, a critical region for fear inhibition, would lead to enhanced conditioned safety memory. Male Sprague Dawley rats were equipped with osmotic mini-pumps attached to an infusion cannula aimed at the IL. Mini-pumps were either filled with the glutamate decarboxylase (GAD) inhibitor l-allylglycine (l-AG) or the inactive enantiomer d-allylglycine (d-AG). Previous studies demonstrated that chronic infusions of l-AG lead to lower GABA levels and overall enhanced neural activity. The effect of IL disinhibition on conditioned safety was investigated utilizing the acoustic startle response. Chronic disinhibition of the IL facilitated conditioned safety memory, along with reduced contextual fear and lower corticosterone levels. The present findings suggest that the IL is a key brain region for conditioned safety memory. Because anxiety disorder patients are often not capable to use safety cues to inhibit unnecessary fear responses, the present findings are of clinical relevance and could potentially contribute to therapy optimization.
Statin as anti-cancer therapy in autochthonous T-lymphomas expressing stabilized gain-of-function mutant p53 proteins
Authors: Tutuska Karis , Parrilla-Monge Laura , Di Cesare Erica , Nemajerova Alice , Moll Ute M.
Published: April 2020

An important component of missense mutant p53 gain-of-function (mutp53 GOF) activities is the ability of stabilized mutp53 proteins to upregulate the mevalonate pathway, providing a rationale for exploring the statin family of HMG-CoA reductase inhibitors as anticancer agents in mutp53 tumors. In this small exploratory study we report on the effects of statin treatment in autochthonous mouse models of clinically advanced T-cell lymphoma expressing two different GOF mutp53 alleles. We find that Rosuvastatin monotherapy shows a modest, p53 allele-selective and transient anti-tumor effect in autochthonous T-lymphomas expressing the p53 R248Q DNA contact mutant, but not in tumors expressing the p53 R172H conformational mutant. p53 null mice also do not benefit. In vitro statin sensitivity is not a strong predictor for in vivo sensitivity, while subcutaneous allografts are. Future explorations of statins in combination therapies are justified to improve its anti-tumor effects and to better define the most statin-sensitive alleles and tumor types among mutp53-stabilized cancers.
LncRNA KCNQ1OT1 sponges miR-34c-5p to promote osteosarcoma growth via ALDOA enhanced aerobic glycolysis
Authors: Shen Yifei , Xu Jingwen , Pan Xiaohui , Zhang Yunkun , Weng Yiping , Zhou Dong , He Shisheng
Published: April 2020

Metabolic switch from oxidative phosphorylation to aerobic glycolysis, which is also called the Warburg effect, is a hallmark of osteosarcoma (OS) and leads to the enhancement of cell chemoresistance, growth, metastasis, and invasion. Emerging evidence indicates that long non-coding RNA (lncRNA) plays a crucial role in the Warburg effect of cancer cells. Here, we report that lncRNA KCNQ1OT1 was upregulated in OS. Meanwhile, functional experiments demonstrated that the KCNQ1OT1 facilitated proliferation and suppressed apoptosis of OS cells. In addition, KCNQ1OT1 contributed to the Warburg effect by stimulating aldolase A (ALDOA) expression. Furthermore, using bioinformatics analysis, luciferase reporter, RNA immunoprecipitation, and RNA pull-down assay, we identified that KCNQ1OT1 functions as a competing endogenous RNA (ceRNA) by sponging miR-34c-5p, which inhibited ALDOA expression by directly targeting its 3ʹUTR. Taken together, these data identified a key role of KCNQ1OT1 in glucose metabolism reprogramming of OS. Targeting the KCNQ1OT1/miR-34c-5p/ALDOA axis may be a potential therapeutic target in OS treatment.
Escape mutations circumvent a tradeoff between resistance to a beta-lactam and resistance to a beta-lactamase inhibitor
Authors: Russ Dor , Glaser Fabian , Shaer Tamar Einat , Yelin Idan , Baym Michael , Kelsic Eric D. , Zampaloni Claudia , Haldimann Andreas , Kishony Roy
Published: April 2020

Beta-lactamase inhibitors are increasingly used to counteract antibiotic resistance mediated by beta-lactamase enzymes. These inhibitors compete with the beta-lactam antibiotic for the same binding site on the beta-lactamase, thus generating an evolutionary tradeoff: mutations that increase the enzyme’s beta-lactamase activity tend to increase also its susceptibility to the inhibitor. Here, we investigate how common and accessible are mutants that escape this adaptive tradeoff. Screening a deep mutant library of theblaampCbeta-lactamase gene ofEscherichia coli, we identified mutations that allow growth at beta-lactam concentrations far exceeding those inhibiting growth of the wildtype strain, even in the presence of the enzyme inhibitor (avibactam). These escape mutations are rare and drug-specific, and some combinations of avibactam with beta-lactam drugs appear to prevent such escape phenotypes. Our results, showing differential adaptive potential ofblaampCto combinations of avibactam and different beta-lactam antibiotics, suggest that it may be possible to identify treatments that are more resilient to evolution of resistance.
Methylation of Salmonella Typhimurium flagella promotes bacterial adhesion and host cell invasion
Authors: Horstmann Julia A. , Lunelli Michele , Cazzola Hélène , Heidemann Johannes , Kühne Caroline , Steffen Pascal , Szefs Sandra , Rossi Claire , Lokareddy Ravi K. , Wang Chu , Lemaire Laurine , Hughes Kelly T. , Uetrecht Charlotte , Schlüter Hartmut , Grassl Guntram A. , Stradal Theresia E. B. , Rossez Yannick , Kolbe Michael , Erhardt Marc
Published: April 2020

The long external filament of bacterial flagella is composed of several thousand copies of a single protein, flagellin. Here, we explore the role played by lysine methylation of flagellin in Salmonella, which requires the methylase FliB. We show that both flagellins of Salmonella enterica serovar Typhimurium, FliC and FljB, are methylated at surface-exposed lysine residues by FliB. A Salmonella Typhimurium mutant deficient in flagellin methylation is outcompeted for gut colonization in a gastroenteritis mouse model, and methylation of flagellin promotes bacterial invasion of epithelial cells in vitro. Lysine methylation increases the surface hydrophobicity of flagellin, and enhances flagella-dependent adhesion of Salmonella to phosphatidylcholine vesicles and epithelial cells. Therefore, posttranslational methylation of flagellin facilitates adhesion of Salmonella Typhimurium to hydrophobic host cell surfaces, and contributes to efficient gut colonization and host infection.
HyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells
Authors: Nguyen Diu T. T. , Lu Yuheng , Chu Eren L. , Yang Xuejing , Park Sun-Mi , Choo Zi-Ning , Chin Christopher R. , Prieto Camila , Schurer Alexandra , Barin Ersilia , Savino Angela M. , Gourkanti Saroj , Patel Payal , Vu Ly P. , Leslie Christina S. , Kharas Michael G.
Published: April 2020

The cell-context dependency for RNA binding proteins (RBPs) mediated control of stem cell fate remains to be defined. Here we adapt the HyperTRIBE method using an RBP fused to a Drosophila RNA editing enzyme (ADAR) to globally map the mRNA targets of the RBP MSI2 in mammalian adult normal and malignant stem cells. We reveal a unique MUSASHI-2 (MSI2) mRNA binding network in hematopoietic stem cells that changes during transition to multipotent progenitors. Additionally, we discover a significant increase in RNA binding activity of MSI2 in leukemic stem cells compared with normal hematopoietic stem and progenitor cells, resulting in selective regulation of MSI2’s oncogenic targets. This provides a basis for MSI2 increased dependency in leukemia cells compared to normal cells. Moreover, our study provides a way to measure RBP function in rare cells and suggests that RBPs can achieve differential binding activity during cell state transition independent of gene expression.
Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity
Authors: He Yonghan , Zhang Xuan , Chang Jianhui , Kim Ha-Neui , Zhang Peiyi , Wang Yingying , Khan Sajid , Liu Xingui , Zhang Xin , Lv Dongwen , Song Lin , Li Wen , Thummuri Dinesh , Yuan Yaxia , Wiegand Janet S. , Ortiz Yuma T. , Budamagunta Vivekananda , Elisseeff Jennifer H. , Campisi Judith , Almeida Maria , Zheng Guangrong , Zhou Daohong
Published: April 2020

Small molecules that selectively kill senescent cells (SCs), termed senolytics, have the potential to prevent and treat various age-related diseases and extend healthspan. The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity. Here, we report the use of proteolysis-targeting chimera (PROTAC) technology to reduce the platelet toxicity of navitoclax (also known as ABT263), a Bcl-2 and Bcl-xl dual inhibitor, by converting it into PZ15227 (PZ), a Bcl-xl PROTAC, which targets Bcl-xl to the cereblon (CRBN) E3 ligase for degradation. Compared to ABT263, PZ is less toxic to platelets, but equally or slightly more potent against SCs because CRBN is poorly expressed in platelets. PZ effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia. With further improvement, Bcl-xl PROTACs have the potential to become safer and more potent senolytic agents than Bcl-xl inhibitors.
Ethanol consumption inhibits TFH cell responses and the development of autoimmune arthritis
Authors: Azizov Vugar , Dietel Katharina , Steffen Franziska , Dürholz Kerstin , Meidenbauer Julia , Lucas Sébastien , Frech Michael , Omata Yasunori , Tajik Narges , Knipfer Lisa , Kolenbrander Anne , Seubert Silvia , Lapuente Dennis , Sokolova Maria V. , Hofmann Jörg , Tenbusch Matthias , Ramming Andreas , Steffen Ulrike , Nimmerjahn Falk , Linker Ralf , Wirtz Stefan , Herrmann Martin , Temchura Vladimir , Sarter Kerstin , Schett Georg , Zaiss Mario M.
Published: April 2020

Alcohol consumption is a consistent protective factor for the development of autoimmune diseases such as rheumatoid arthritis (RA). The underlying mechanism for this tolerance-inducing effect of alcohol, however, is unknown. Here we show that alcohol and its metabolite acetate alter the functional state of T follicular helper (TFH) cells in vitro and in vivo, thereby exerting immune regulatory and tolerance-inducing properties. Alcohol-exposed mice have reduced Bcl6 and PD-1 expression as well as IL-21 production by TFHcells, preventing proper spatial organization of TFHcells to form TFH:B cell conjugates in germinal centers. This effect is associated with impaired autoantibody formation, and mitigates experimental autoimmune arthritis. By contrast, T cell independent immune responses and passive models of arthritis are not affected by alcohol exposure. These data clarify the immune regulatory and tolerance-inducing effect of alcohol consumption.
The vaginal microbiota associates with the regression of untreated cervical intraepithelial neoplasia 2 lesions
Authors: Mitra Anita , MacIntyre David A. , Ntritsos George , Smith Ann , Tsilidis Konstantinos K. , Marchesi Julian R. , Bennett Phillip R. , Moscicki Anna-Barbara , Kyrgiou Maria
Published: April 2020

Emerging evidence suggests associations between the vaginal microbiota (VMB) composition, human papillomavirus (HPV) infection, and cervical intraepithelial neoplasia (CIN); however, causal inference remains uncertain. Here, we use bacterial DNA sequencing from serially collected vaginal samples from a cohort of 87 adolescent and young women aged 16–26 years with histologically confirmed, untreated CIN2 lesions to determine whether VMB composition affects rates of regression over 24 months. We show that women with a Lactobacillus-dominant microbiome at baseline are more likely to have regressive disease at 12 months. Lactobacillus spp. depletion and presence of specific anaerobic taxa including Megasphaera, Prevotella timonensis and Gardnerella vaginalis are associated with CIN2 persistence and slower regression. These findings suggest that VMB composition may be a future useful biomarker in predicting disease outcome and tailoring surveillance, whilst it may offer rational targets for the development of new prevention and treatment strategies.
Changing role of coral reef marine reserves in a warming climate
Authors: Graham Nicholas A. J. , Robinson James P. W. , Smith Sarah E. , Govinden Rodney , Gendron Gilberte , Wilson Shaun K.
Published: April 2020

Coral reef ecosystems are among the first to fundamentally change in structure due to climate change, which leads to questioning of whether decades of knowledge regarding reef management is still applicable. Here we assess ecological responses to no-take marine reserves over two decades, spanning a major climate-driven coral bleaching event. Pre-bleaching reserve responses were consistent with a large literature, with higher coral cover, more species of fish, and greater fish biomass, particularly of upper trophic levels. However, in the 16 years following coral mortality, reserve effects were absent for the reef benthos, and greatly diminished for fish species richness. Positive fish biomass effects persisted, but the groups of fish benefiting from marine reserves profoundly changed, with low trophic level herbivores dominating the responses. These findings highlight that while marine reserves still have important roles on coral reefs in the face of climate change, the species and functional groups they benefit will be substantially altered.
Topography and human pressure in mountain ranges alter expected species responses to climate change
Authors: Elsen Paul R. , Monahan William B. , Merenlender Adina M.
Published: April 2020

Climate change is leading to widespread elevational shifts thought to increase species extinction risk in mountains. We integrate digital elevation models with a metric of human pressure to examine changes in the amount of intact land area available for species undergoing elevational range shifts in all major mountain ranges globally (n = 1010). Nearly 60% of mountainous area is under intense human pressure, predominantly at low elevations and mountain bases. Consequently, upslope range shifts generally resulted in modeled species at lower elevations expanding into areas of lower human pressure and, due to complex topography, encountering more intact land area relative to their starting position. Such gains were often attenuated at high elevations as land-use constraints diminished and topographic constraints increased. Integrating patterns of topography and human pressure is essential for accurate species vulnerability assessments under climate change, as priorities for protecting, connecting, and restoring mountain landscapes may otherwise be misguided.
Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts
Authors: Kim Kwanghee , Hu Wenhuo , Audenet François , Almassi Nima , Hanrahan Aphrothiti J. , Murray Katie , Bagrodia Aditya , Wong Nathan , Clinton Timothy N. , Dason Shawn , Mohan Vishnu , Jebiwott Sylvia , Nagar Karan , Gao Jianjiong , Penson Alex , Hughes Chris , Gordon Benjamin , Chen Ziyu , Dong Yiyu , Watson Philip A. , Alvim Ricardo , Elzein Arijh , Gao Sizhi P. , Cocco Emiliano , Santin Alessandro D. , Ostrovnaya Irina , Hsieh James J. , Sagi Irit , Pietzak Eugene J. , Hakimi A. Ari , Rosenberg Jonathan E. , Iyer Gopa , Vargas Herbert A. , Scaltriti Maurizio , Al-Ahmadie Hikmat , Solit David B. , Coleman Jonathan A.
Published: April 2020

Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.
Voltage- and time-dependent valence state transition in cobalt oxide catalysts during the oxygen evolution reaction
Authors: Zhou Jing , Zhang Linjuan , Huang Yu-Cheng , Dong Chung-Li , Lin Hong-Ji , Chen Chien-Te , Tjeng L. H. , Hu Zhiwei
Published: April 2020

The ability to determine the electronic structure of catalysts during electrochemical reactions is highly important for identification of the active sites and the reaction mechanism. Here we successfully applied soft X-ray spectroscopy to follow in operando the valence and spin state of the Co ions in Li2Co2O4 under oxygen evolution reaction (OER) conditions. We have observed that a substantial fraction of the Co ions undergo a voltage-dependent and time-dependent valence state transition from Co3+ to Co4+ accompanied by spontaneous delithiation, whereas the edge-shared Co–O network and spin state of the Co ions remain unchanged. Density functional theory calculations indicate that the highly oxidized Co4+ site, rather than the Co3+ site or the oxygen vacancy site, is mainly responsible for the high OER activity.
A vaccine-based nanosystem for initiating innate immunity and improving tumor immunotherapy
Authors: Zheng Di-Wei , Gao Fan , Cheng Qian , Bao Peng , Dong Xue , Fan Jin-Xuan , Song Wen , Zeng Xuan , Cheng Si-Xue , Zhang Xian-Zheng
Published: April 2020

The unsatisfactory response rate of immune checkpoint blockade (ICB) immunotherapy severely limits its clinical application as a tumor therapy. Here, we generate a vaccine-based nanosystem by integrating siRNA for Cd274 into the commercial human papillomavirus (HPV) L1 (HPV16 L1) protein. This nanosystem has good biosafety and enhances the therapeutic response rate of anti-tumor immunotherapy. The HPV16 L1 protein activates innate immunity through the type I interferon pathway and exhibits an efficient anti-cancer effect when cooperating with ICB therapy. For both resectable and unresectable breast tumors, the nanosystem decreases 71% tumor recurrence and extends progression-free survival by 67%. Most importantly, the nanosystem successfully induces high response rates in various genetically modified breast cancer models with different antigen loads. The strong immune stimulation elicited by this vaccine-based nanosystem might constitute an approach to significantly improve current ICB immunotherapy.
Synthesis of high-entropy alloy nanoparticles on supports by the fast moving bed pyrolysis
Authors: Gao Shaojie , Hao Shaoyun , Huang Zhennan , Yuan Yifei , Han Song , Lei Lecheng , Zhang Xingwang , Shahbazian-Yassar Reza , Lu Jun
Published: April 2020

High-entropy alloy nanoparticles (HEA-NPs) are important class of materials with significant technological potential. However, the strategies for synthesizing uniformly dispersed HEA-NPs on granular supports such as carbon materials, γ-Al2O3, and zeolite, which is vital to their practical applications, are largely unexplored. Herein, we present a fast moving bed pyrolysis strategy to immobilize HEA-NPs on granular supports with a narrow size distribution of 2 nm up to denary (MnCoNiCuRhPdSnIrPtAu) HEA-NPs at 923 K. Fast moving bed pyrolysis strategy ensures the mixed metal precursors rapidly and simultaneously pyrolyzed at high temperatures, resulting in nuclei with a small size. The representative quinary (FeCoPdIrPt) HEA-NPs exhibit high stability (150 h) toward hydrogen evolution reaction with high mass activity, which is 26 times higher than the commercial Pt/C at an overpotential of 100 mV. Our strategy provides an improved methodology for synthesizing HEA-NPs on various supports.
Identification of therapeutics that target eEF1A2 and upregulate utrophin A translation in dystrophic muscles
Authors: Péladeau Christine , Adam Nadine , Bronicki Lucas M. , Coriati Adèle , Thabet Mohamed , Al-Rewashdy Hasanen , Vanstone Jason , Mears Alan , Renaud Jean-Marc , Holcik Martin , Jasmin Bernard J.
Published: April 2020

Up-regulation of utrophin in muscles represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy. We previously demonstrated that eEF1A2 associates with the 5’UTR of utrophin A to promote IRES-dependent translation. Here, we examine whether eEF1A2 directly regulates utrophin A expression and identify via an ELISA-based high-throughput screen, FDA-approved drugs that upregulate both eEF1A2 and utrophin A. Our results show that transient overexpression of eEF1A2 in mouse muscles causes an increase in IRES-mediated translation of utrophin A. Through the assessment of our screen, we reveal 7 classes of FDA-approved drugs that increase eEF1A2 and utrophin A protein levels. Treatment of mdx mice with the 2 top leads results in multiple improvements of the dystrophic phenotype. Here, we report that IRES-mediated translation of utrophin A via eEF1A2 is a critical mechanism of regulating utrophin A expression and reveal the potential of repurposed drugs for treating DMD via this pathway.
BCL9/STAT3 regulation of transcriptional enhancer networks promote DCIS progression
Authors: Elsarraj Hanan S. , Hong Yan , Limback Darlene , Zhao Ruonan , Berger Jenna , Bishop Stephanie C. , Sabbagh Aria , Oppenheimer Linzi , Harper Haleigh E. , Tsimelzon Anna , Huang Shixia , Hilsenbeck Susan G. , Edwards Dean P. , Fontes Joseph , Fan Fang , Madan Rashna , Fangman Ben , Ellis Ashley , Tawfik Ossama , Persons Diane L. , Fields Timothy , Godwin Andrew K. , Hagan Christy R. , Swenson-Fields Katherine , Coarfa Cristian , Thompson Jeffrey , Behbod Fariba
Published: April 2020

The molecular processes by which some human ductal carcinoma in situ (DCIS) lesions advance to the more aggressive form, while others remain indolent, are largely unknown. Experiments utilizing a patient-derived (PDX) DCIS Mouse INtraDuctal (MIND) animal model combined with ChIP-exo and RNA sequencing revealed that the formation of protein complexes between B Cell Lymphoma-9 (BCL9), phosphoserine 727 STAT3 (PS-727-STAT3) and non-STAT3 transcription factors on chromatin enhancers lead to subsequent transcription of key drivers of DCIS malignancy. Downregulation of two such targets, integrin β3 and its associated metalloproteinase, MMP16, resulted in a significant inhibition of DCIS invasive progression. Finally, in vivo targeting of BCL9, using rosemary extract, resulted in significant inhibition of DCIS malignancy in both cell line and PDX DCIS MIND animal models. As such, our studies provide compelling evidence for future testing of rosemary extract as a chemopreventive agent in breast cancer.
Ab initio theory of the negatively charged boron vacancy qubit in hexagonal boron nitride
Authors: Ivády Viktor , Barcza Gergely , Thiering Gergő , Li Song , Hamdi Hanen , Chou Jyh-Pin , Legeza Örs , Gali Adam
Published: April 2020

Highly correlated orbitals coupled with phonons in two-dimension are identified for paramagnetic and optically active boron vacancy in hexagonal boron nitride by first principles methods which are responsible for recently observed optically detected magnetic resonance signal. Here, we report ab initio analysis of the correlated electronic structure of this center by density matrix renormalization group and Kohn-Sham density functional theory methods. By establishing the nature of the bright and dark states as well as the position of the energy levels, we provide a complete description of the magneto-optical properties and corresponding radiative and non-radiative routes which are responsible for the optical spin polarization and spin dependent luminescence of the defect. Our findings pave the way toward advancing the identification and characterization of room temperature quantum bits in two-dimensional solids.
Genetic predispositions of Parkinson’s disease revealed in patient-derived brain cells
Authors: Tran Jenne , Anastacio Helena , Bardy Cedric
Published: April 2020

Parkinson’s disease (PD) is the second most prevalent neurological disorder and has been the focus of intense investigations to understand its etiology and progression, but it still lacks a cure. Modeling diseases of the central nervous system in vitro with human induced pluripotent stem cells (hiPSC) is still in its infancy but has the potential to expedite the discovery and validation of new treatments. Here, we discuss the interplay between genetic predispositions and midbrain neuronal impairments in people living with PD. We first summarize the prevalence of causal Parkinson’s genes and risk factors reported in 74 epidemiological and genomic studies. We then present a meta-analysis of 385 hiPSC-derived neuronal lines from 67 recent independent original research articles, which point towards specific impairments in neurons from Parkinson’s patients, within the context of genetic predispositions. Despite the heterogeneous nature of the disease, current iPSC models reveal converging molecular pathways underlying neurodegeneration in a range of familial and sporadic forms of Parkinson’s disease. Altogether, consolidating our understanding of robust cellular phenotypes across genetic cohorts of Parkinson’s patients may guide future personalized drug screens in preclinical research.
Publisher Correction: Turning charge-density waves into Cooper pairs
Authors: Chikina Alla , Fedorov Alexander , Bhoi Dilipkumar , Voroshnin Vladimir , Haubold Erik , Kushnirenko Yevhen , Kim Kee Hoon , Borisenko Sergey
Published: April 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Functional arrays of human pluripotent stem cell-derived cardiac microtissues
Authors: Thavandiran Nimalan , Hale Christopher , Blit Patrick , Sandberg Mark L. , McElvain Michele E. , Gagliardi Mark , Sun Bo , Witty Alec , Graham George , Do Van T.H. , Bakooshli Mohsen Afshar , Le Hon , Ostblom Joel , McEwen Samuel , Chau Erik , Prowse Andrew , Fernandes Ian , Norman Andreea , Gilbert Penney M. , Keller Gordon , Tagari Philip , Xu Han , Radisic Milica , Zandstra Peter W.
Published: April 2020

To accelerate the cardiac drug discovery pipeline, we set out to develop a platform that would be capable of quantifying tissue-level functions such as contractile force and be amenable to standard multiwell-plate manipulations. We report a 96-well-based array of 3D human pluripotent stem cell (hPSC)-derived cardiac microtissues - termed Cardiac MicroRings (CaMiRi) - in custom 3D-print-molded multiwell plates capable of contractile force measurement. Within each well, two elastomeric microcantilevers are situated above a circumferential ramp. The wells are seeded with cell-laden collagen, which, in response to the gradual slope of the circumferential ramp, self-organizes around tip-gated microcantilevers to form contracting CaMiRi. The contractile force exerted by the CaMiRi is measured and calculated using the deflection of the cantilevers. Platform responses were robust and comparable across wells, and we used it to determine an optimal tissue formulation. We validated the contractile force response of CaMiRi using selected cardiotropic compounds with known effects. Additionally, we developed automated protocols for CaMiRi seeding, image acquisition, and analysis to enable the measurement of contractile force with increased throughput. The unique tissue fabrication properties of the platform, and the consequent effects on tissue function, were demonstrated upon adding hPSC-derived epicardial cells to the system. This platform represents an open-source contractile force screening system useful for drug screening and tissue engineering applications.