bluuebunny/crossref_metadata_2025 huggingface dataset:
140 Effects of Long-Term Valbenazine on Tardive Dyskinesia in KINECT 4: Post Hoc Response and Shift Analyses
Authors: Marder Stephen R. , Comella Cynthia L. , Singer Carlos , Farahmand Khodayar , Jimenez Roland
Published: April 2020

Study Objective:

Valbenazine (VBZ) is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged antipsychotic exposure. Post hoc response and shift analyses were conducted using Abnormal Involuntary Movement Scale (AIMS) data from KINECT 4 (NCT02405091), a long-term open-label study in which participants received up to 48 weeks of open-label treatment with once-daily VBZ (40 or 80 mg).

Methods:

KINECT 4 included participants who met the following criteria: ages 18 to 85 years; DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or mood disorder; neuroleptic-induced TD for ≥3 months prior to screening; stable psychiatric status (Brief Psychiatric Rating Scale score <50); no high risk of active suicidal ideation or behavior. Stable doses of concomitant medications to treat psychiatric and medical disorders were allowed. VBZ dosing was initiated at 40 mg, with escalation to 80 mg at Week 4 based on clinical assessment of TD and tolerability; a dose reduction to 40 mg was allowed if 80 mg was not tolerated. AIMS responses, ranging from ≥10% to 100% improvement from baseline in AIMS total score (sum of items 1-7), were analyzed at Week 48 based on scoring by site investigators. AIMS shift, conducted for each item (representing 7 different body regions), was defined as an improvement from a score ≥3 (moderate/severe) at baseline to a score ≤2 (none/minimal/mild) at Week 48.

Results:

103 participants had an available AIMS assessment at Week 48 (40 mg, n=20; 80 mg, n=83 [including 9 with a dose reduction]). At Week 48, 94.2% of participants had ≥30% total AIMS score improvement (40 mg, 90.0%; 80 mg, 95.2%) and 86.4% had ≥50% improvement (40 mg, 90.0%; 80 mg, 85.5%). The percentage of participants meeting the remaining AIMS response thresholds ranged from 9.7% (for 100% response) to 97.1% (for ≥10% response). In participants who had an AIMS item score ≥3 at baseline, shifts to a score ≤2 at Week 48 were as follows: 100% for lips, upper extremities, and lower extremities (VBZ 40 mg and 80 mg). Shift rates for the remaining regions were as follows (40 mg, 80 mg): face (100% [9/9], 96.9% [31/32]), jaw (100% [10/10], 97.6% [40/41]), tongue (100% [11/11], 97.9% [47/48]), trunk (87.5% [7/8], 88.9% [16/18]).

Conclusions:

After 48 weeks of treatment with once-daily VBZ (40 or 80 mg), >85% of KINECT 4 participants had a clinically meaningful AIMS response (≥30% total score improvement), a robust AIMS response (≥50% total score improvement), or an AIMS shift (from item score ≥3 at baseline to score ≤2 at Week 48). These results suggest that VBZ is an appropriate long-term treatment for many adults with TD.

Funding Acknowledgements:

This study was sponsored by Neurocrine Biosciences, Inc.
144 Esketamine Nasal Spray for Management of Treatment-Resistant Depression: Number Needed to Treat, Number Needed to Harm, Likelihood to be Helped/Harmed
Authors: Citrome Leslie , DiBernardo Allitia , Singh Jaskaran
Published: April 2020

Background:

Targeting of glutamate receptors is a novel approach for the treatment of major depressive disorder (MDD). This study aimed to review the usefulness for esketamine nasal spray for the management of treatment-resistant depression (TRD) using the tools of evidence-based medicine: number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).

Methods:

Data sources were four completed Phase 3 randomized, double-blind, placebo-controlled, studies, including two pivotal registration studies of esketamine nasal spray in TRD in non-elderly adults (acute flexible-dose study NCT02418585, maintenance study NCT02493868) Efficacy outcomes included acute response (≥50% decrease from baseline on Montgomery-Asberg Depression Rating Scale [MADRS] total score), acute remission (MADRS scores ≤12; and other thresholds using the MADRS and Clinical Global Impressions-Severity [CGI-S] scales), categorical shifts in MADRS and CGI-S scores, and avoidance of relapse/recurrence (observed relapse rates). NNT, NNH and LLH are calculated for combination of esketamine nasal spray and oral antidepressant (esketamine+AD) vs AD+placebo in patients with TRD.

Results:

In the acute flexible-dose study of esketamine nasal spray (56-84 mg twice-weekly for 4 weeks), MADRS response with esketamine+AD vs AD+placebo at endpoint (rates 63.4% vs 49.5%, respectively) yielded an NNT value of 8, and MADRS remission at endpoint (48.2% vs 30.3%) resulted in a NNT vs AD+placebo of 6. NNH values vs AD+placebo were <10 for the adverse events (AE) of dissociation (26.1% vs 3.7%), vertigo (26.1% vs 2.8%), nausea (26.1% vs 6.4%), dizziness (20.9% vs 4.6%), and dysgeusia (24.3% vs 11.9%), the NNH values were 5, 5, 6, 7, and 9, respectively. Discontinuation rates due to AE (7.0% vs 0.9%) yielded a NNH of 17. LHH comparing MADRS remission vs discontinuation was 17/6, or approximately 3. The pattern of results was similar for the other acute studies and for the pooled data combining all 3 acute studies. Maintenance use of esketamine (dose 56-84 mg once-weekly or once-every-other-week) plus an oral AD demonstrated NNT values <10 for relapse and/or maintenance of remission in favor of esketamine+AD vs AD+placebo, a NNT of 4 was observed for outcome of relapse in patients with stable response at the time of randomization (relapse rates were 25.8% vs 57.6%, respectively). In the maintenance study, discontinuation rates due to an AE (2.6% vs 2.1%) yielded a non-significant NNH value of 178.

Conclusion:

The low NNT values <10 for efficacy outcomes suggest potential benefits of esketamine+AD for both acute and maintenance use. LHH was favorable: esketamine+AD was 3 times more likely to result in acute remission vs discontinuation due to an AE.

Funding Acknowledgements:

Janssen Global Services, LLC
147 Training Forgiveness. A Novel Approach to Reducing Physician Burnout
Authors: Firulescu Lidia , May Ross W. , Fincham Frank D. , Arocha Emelina A. , Sanchez-Gonzalez Marcos A.
Published: April 2020

Study Objective:

Psychological risk factors that lead to impaired work performance, negatively impacting mental and physical health, have emerged as a concern across clinical settings. Although depression and anxiety are linked to poor physician mental health, physician burnout characterized by work related stress due to chronic exhaustion from clinical work, cynicism toward meaning of the medical profession, and feelings of inadequacy toward work related accomplishments, may be an even stronger indicator of well-being. Literature suggests that work satisfaction among physicians is rapidly deteriorating owing to high rates of burnout and poor mental health. Although the relationship between work burnout (WB) and negative affectivity has been well documented, the association with positive affect, such as trait forgiveness (TF) has been overlooked. On that note, research shows that lifetime stress severity and lower levels of forgiveness predict worse mental and physical health. Since TF has been linked strongly with healthy workplace relationships, positive occupational outcomes and general well-being, its association with WB remains to be investigated. Therefore, the aim of the present study was to explore the link between TF and WB among physicians. We hypothesized that TF would be associated with reduced levels of burnout.

Method:

A total of 62 (F=23) medical residents at a Teaching Hospital consented for the study. Residents were administered surveys on WB (Maslach Burnout Inventory), workplace bullying, personal bullying (PB), interpersonal rejection sensitivity (IRS), perceived stress scale (PSS), TF, anxiety, and depression, all of which were anonymously submitted via electronically. Hierarchical multiple regression (HMR) models were used to determine the associations between WB, work environment social factors and TF. A p-value of <0.05 was considered significant.

Results:

The mean age 33.1 ± SD 4.2 years. HMR analysis using WB as main outcome contained 6 predictors: Model 1 contained depression and anxiety, Model 2 added PB, Model 3 added IRS and PSS, Model 4 added TF. Anxiety and TF were the only significant predictors (p= >0.05) accounting for 10.4% and 17.5% of the variance in WB scores, respectively.

Conclusions:

The novel finding of the present study is that TF was associated with low levels of burnout. Additionally, WB was found to be linked to anxiety and depression which is in line with previous research. These data suggest that TF could be a potential resolution to the deleterious influence of burnout. Further exploration is needed in order to understand the psychology of forgiveness as a potential adjuvant and/or therapeutic intervention for physicians’ burnout. These results suggest that strategies including forgiveness training aimed at decreasing WB while increasing job satisfaction among physicians warrant further exploration.
151 Confirmed Safety of Deutet.rabenazine for Tardive Dyskinesia in a 3-Year Open-Label Extension Study
Authors: Fernandez Hubert H. , Barkay Hadas , Hauser Robert A. , Factor Stewart A. , Jimenez-Shahed Joohi , Gross Nicholas , Marinelli Leslie , Gordon Mark Forrest , Savola Juha-Matti , Anderson Karen E.
Published: April 2020

Background:

Deutetrabenazine (Austedo) is approved by the FDA for treatment of tardive dyskinesia (TD) in adults. In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores compared with placebo, and there were low rates of overall adverse events (AEs) and discontinuations associated with deutetrabenazine. The objective of this study was to evaluate the long-term safety and tolerability of deutetrabenazine in patients with TD at 3 years.

METHODS:

Patients who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12 mg/day, titrating up to a maximum total daily dose of 48 mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safety measures included incidence of AEs, serious AEs (SAEs), and AEs leading to withdrawal, dose reduction, or dose suspension. Exposure-adjusted incidence rates (EAIRs; incidence/patient-years) were used for calculating AE frequencies. This analysis reports results up to Week 158.

RESULTS:

A total of 343 patients were enrolled (111 received placebo and 232 received deutetrabenazine in the parent studies). At the time of this analysis, 183 patients were still receiving treatment; 259 completed 1 year, 172 completed 2 years, and 41 completed 3 years. There were 623 patient-years of exposure. More than 40% of patients reached the maximum dose. EAIRs of AEs were comparable to or lower than those observed in the ARM-TD and AIM-TD short-term randomized trials of deutetrabenazine vs. placebo. The frequency of SAEs (EAIR 0.10) was similar to that observed with short-term placebo (0.33) and short-term deutetrabenazine (range 0.06–0.33) treatment. AEs leading to withdrawal (0.06), dose reduction (0.10), and dose suspension (0.05) were uncommon.

CONCLUSION:

These results support the safety outcomes observed in the ARM-TD and AIM-TD parent studies and the safety of deutetrabenazine for long-term use in patients with TD.

Funding Acknowledgements: This study was funded by Teva Pharmaceuticals, Petach Tikva, Israel
Inhibitory effects of bioaccessible anthocyanins and procyanidins from apple, red grape, cinnamon on α-amylase, α-glucosidase and lipase
Authors: Ercan Pınar , El Sedef Nehir
Published: April 2020

Abstract. The goals of this study were to determine and evaluate the bioaccessibility of total anthocyanin and procyanidin in apple (Amasya, Malus communis), red grape (Papazkarası, Vitis vinifera) and cinnamon (Cassia, Cinnamomum) using an in vitro static digestion system based on human gastrointestinal physiologically relevant conditions. Also, in vitro inhibitory effects of these foods on lipid (lipase) and carbohydrate digestive enzymes (α-amylase and α-glucosidase) were performed with before and after digested samples using acarbose and methylumbelliferyl oleate (4MUO) as the positive control. While the highest total anthocyanin content was found in red grape (164 ± 2.51 mg/100 g), the highest procyanidin content was found in cinnamon (6432 ± 177.31 mg/100 g) (p < 0.05). The anthocyanin bioaccessibilities were found as 10.2 ± 1%, 8.23 ± 0.64%, and 8.73 ± 0.70% in apple, red grape, and cinnamon, respectively. The procyanidin bioaccessibilities of apple, red grape, and cinnamon were found as 17.57 ± 0.71%, 14.08 ± 0.74% and 18.75 ± 1.49%, respectively. The analyzed apple, red grape and cinnamon showed the inhibitory activity against α-glucosidase (IC50 544 ± 21.94, 445 ± 15.67, 1592 ± 17.58 μg/mL, respectively), α-amylase (IC50 38.4 ± 7.26, 56.1 ± 3.60, 3.54 ± 0.86 μg/mL, respectively), and lipase (IC50 52.7 ± 2.05, 581 ± 54.14, 49.6 ± 2.72 μg/mL), respectively. According to our results apple, red grape and cinnamon have potential to inhibit of lipase, α-amylase and α-glucosidase digestive enzymes.
The Recovery Process for Individuals With Schizophrenia in the	Context of Evidence-Based Psychotherapy and Rehabilitation
Authors: Rakitzi Stavroula , Georgila Polyxeni , Becker-Woitag Astrid Prabala
Published: April 2020

Abstract. This systematic review aimed to evaluate the efficacy of Cognitive Behavioral Therapy (CBT), META Cognitive Therapy (MCT), Metacognitive Training (MCTR), Metacognitive Reflection and Insight Therapy (MERIT), of various rehabilitation programs and of recovery programs in schizophrenia. Medline/Pubmed was searched for studies published in English from January 2010 to August 2018, which were screened against inclusion criteria by two reviewers. The methodological quality of the included studies was evaluated by two independent raters, which are the Effective Public Health Practice Project (EPHPP) quality assessment tool for quantitative studies and the fidelity criteria. The study included 41 RCTs and 12 case studies with n = 3,059 persons with schizophrenia. Cognitive Behavioral Therapy (CBT) proved to be superior in terms of the improvement of primary and secondary outcomes. MCT decreased positive symptoms and improved metacognitive capacity and insight. MCTR reduced positive symptoms and socially disruptive behavior. MERIT improved metacognitive capacity and insight. Rehabilitation programs were efficacious in the improvement of cognition, symptoms, and functional outcome. The recovery programs enhanced illness-management knowledge, attitudes toward medication and insights related to negative symptoms. It is recommended to combine the above evidence based psychotherapeutic interventions. Limitations of this systematic review are discussed toward the end of the essay. Some important factors have to be considered in the future have been mentioned.
Profiles of MBL Cloud and Drizzle Microphysical Properties Retrieved From Ground‐Based Observations and Validated by Aircraft In Situ Measurements Over the Azores
Authors: Wu Peng , Dong Xiquan , Xi Baike , Tian Jingjing , Ward Dale M.
Published: April 2020

The profiles of marine boundary layer (MBL) cloud and drizzle microphysical properties are important for studying the cloud‐to‐rain conversion and growth processes in MBL clouds. However, it is challenging to simultaneously retrieve both cloud and drizzle microphysical properties within an MBL cloud layer using ground‐based observations. In this study, methods were developed to first decompose drizzle and cloud reflectivity in MBL clouds from Atmospheric Radiation Measurement cloud radar reflectivity measurements and then simultaneously retrieve cloud and drizzle microphysical properties during the Aerosol and Cloud Experiments in the Eastern North Atlantic (ACE‐ENA) campaign. These retrieved microphysical properties, such as cloud and drizzle particle size (rc and rm,d), their number concentration (Nc and Nd) and liquid water content (LWCc and LWCd), have been validated by aircraft in situ measurements during ACE‐ENA (~158 hr of aircraft data). The mean surface retrieved (in situ measured) rc, Nc, and LWCc are 10.9 μm (11.8 μm), 70 cm−3 (60 cm−3), and 0.21 g m−3 (0.22 g m−3), respectively. For drizzle microphysical properties, the retrieved (in situ measured) rd, Nd, and LWCd are 44.9 μm (45.1 μm), 0.07 cm−3 (0.08 cm−3), and 0.052 g m−3 (0.066 g m−3), respectively. Treating the aircraft in situ measurements as truth, the estimated median retrieval errors are ~15% for rc, ~35% for Nc, ~30% for LWCc and rd, and ~50% for Nd and LWCd. The findings from this study will provide insightful information for improving our understanding of warm rain processes, as well as for improving model simulations. More studies are required over other climatic regions.
Inconsistent Responses of Transpiration of Different Canopy Layers to Simulated Canopy and Understory N Depositions in a Low‐Subtropical Evergreen Broadleaf Forest
Authors: Li Yanqiong , Zhao Ping , Zhang Zhenzhen , Zhu Liwei , Ouyang Lei , Ni Guangyan
Published: April 2020

Quantifying transpiration and its response to meteorological factors at a stand scale and different canopy layers of forest is important for understanding the hydrological impact of nitrogen (N) deposition on local water balance. For this purpose, sap flows were measured in three upper (Schima superba, Castanea henryi, and Machilus chinensis) and three lower (Symplocos ramosissima, Ilex ficoidea, and Schefflera octophylla) canopy species based on a manipulative experimental platform with canopy (CN) and understory (UN) N additions in a low‐subtropical evergreen broadleaf forest. Each application included concentrations of 0, 25, and 50 kg·ha−1·a−1 N. Results showed that N addition obviously influenced the sap flux density and such influence varied among different species and between canopy layers. Upper canopy species contributed the most transpiration for the whole forest, and CN25 greatly affected the transpiration in both upper and lower canopy layers. Daily water use (Qd) increased logarithmically with daytime average photosynthetically active radiation and daily average vapor pressure deficit. An appropriate canopy N addition (CN25) promoted the Qd and its sensitivity to micrometeorological factors, whereas UN had a minimal effect. These results suggest a substantial difference in response of transpiration to the N addition ways. CN had more effective influence on the canopy transpiration. Thus, UN could not fully reflect the effects of increased N deposition on the canopy‐associated transpiration, and the response of forest transpiration to N deposition needs to be analyzed beyond species and upscaled to the canopy level in favor of meaningful assessments of N deposition.
Tropical Cyclogenesis From Self‐Aggregated Convection in Numerical Simulations of Rotating Radiative‐Convective Equilibrium
Authors: Carstens Jacob D. , Wing Allison A.
Published: April 2020

In a modeled environment of rotating radiative‐convective equilibrium (RCE), convective self‐aggregation may take the form of spontaneous tropical cyclogenesis. We investigate the processes leading to tropical cyclogenesis in idealized simulations with a three‐dimensional cloud‐permitting model configured in rotating RCE, in which the background planetary vorticity is varied across f‐plane cases to represent a range of deep tropical and near‐equatorial environments. Convection is initialized randomly in an otherwise homogeneous environment, with no background wind, precursor disturbance, or other synoptic‐scale forcing. We examine the dynamic and thermodynamic evolution of cyclogenesis in these experiments and compare the physical mechanisms to current theories. All simulations with planetary vorticity corresponding to latitudes from 10°–20° generate intense tropical cyclones, with maximum wind speeds of 80 m s−1 or above. Time to genesis varies widely, even within a five‐member ensemble of 20° simulations, indicating large stochastic variability. Shared across the 10°–20° group is the emergence of a midlevel vortex in the days leading to genesis, which has dynamic and thermodynamic implications on its environment that facilitate the spin‐up of a low‐level vortex. Tropical cyclogenesis is possible in this model at values of Coriolis parameter as low as that representative of 1°. In these experiments, convection self‐aggregates into a quasicircular cluster, which then begins to rotate and gradually strengthen into a tropical storm, aided by strong near‐surface inflow that is already established days prior. Other experiments at these lower Coriolis parameters instead self‐aggregate into a nonrotating elongated band and fail to undergo cyclogenesis over the 100‐day simulation.
Looking Back at Our Pale Blue Dot
Authors: Fogerty Christian
Published: April 2020

Astronomers model changes in Earth’s chemical signature over the past 4 billion years to improve the search for Earth-like exoplanets.
How Financial Markets Can Grow More Climate Savvy
Authors: Duncombe Jenessa
Published: April 2020

Take extreme weather risks into account, and markets could prove hardier in a changing world.
Eurasian Cooling Linked to the Vertical Distribution of Arctic Warming
Authors: He Shengping , Xu Xinping , Furevik Tore , Gao Yongqi
Published: April 2020

Observations show that deep Arctic winter warming, extending from surface to mid‐troposphere, has concurred with below‐average temperature over central Eurasia. Modeling studies focusing on the response to Arctic sea ice loss have shown Arctic surface warming but no consistent atmospheric changes at midlatitude. Using a large number of simulations from coupled and uncoupled climate models, we show that Eurasian below‐average temperatures are more frequent in winters with deep warming compared to shallow, near‐surface warming over the Barents‐Kara Seas. Dramatic weakening of the midlatitude jet stream and increase in Ural blocking frequency are more likely to occur in winters with deep Arctic warming. Deep warming is independent of sea ice forcing but follows increased poleward atmospheric energy and moisture advection from the North Atlantic to the Arctic, indicating that internal natural variability and not sea ice is the main driving forcing for deep Arctic warming‐cold Eurasia pattern in historical simulations.
Constraining Global Changes in Temperature and Precipitation From Observable Changes in Surface Radiative Heating
Authors: Dhara Chirag
Published: April 2020

Changes in the atmospheric composition alter the magnitude and partitioning between the downward propagating solar and atmospheric longwave radiative fluxes heating the Earth's surface. These changes are computed by radiative transfer codes in Global Climate Models and measured with high precision at surface observation networks. Changes in radiative heating signify changes in the global surface temperature and hydrologic cycle. Here, we develop a conceptual framework using an Energy Balance Model to show that first‐order changes in the hydrologic cycle are mainly associated with changes in solar radiation, while those in surface temperature are mainly associated with changes in atmospheric longwave radiation. These insights are used to explain a range of phenomena including observed historical trends, biases in climate model output, and the intermodel spread in climate change projections. These results may help identify biases in future generations of climate models.
Stress Release Process Along an Intraplate Fault Analogous to the Plate Boundary: A Case Study of the 2017 M5.2 Akita‐Daisen Earthquake, NE Japan
Authors: Yoshida Keisuke , Taira Taka'aki , Matsumoto Yoshiaki , Saito Tatsuhiko , Emoto Kentaro , Matsuzawa Toru
Published: April 2020

Stress accumulation and release inside the plate remains poorly understood compared to that at the plate boundaries. Spatiotemporal variations in foreshock and aftershock activities can provide key constraints on time‐dependent stress and deformation processes inside the plate. The 2017 M5.2 Akita‐Daisen intraplate earthquake in NE Japan was preceded by intense foreshock activity and triggered a strong sequence of aftershocks. We examine the spatiotemporal distributions of foreshocks and aftershocks and determine the coseismic slip distribution of the mainshock. Our results indicate that seismicity both before and after the mainshock was concentrated on a planar structure with N‐S strike that dips steeply eastward. We observe a migration of foreshocks toward the mainshock rupture area, suggesting the possibility that foreshocks were triggered by aseismic phenomena preceding the mainshock rupture. The mainshock rupture propagated toward the north, showing less slip beneath foreshock regions. The stress drop of the mainshock was 1.4 MPa, and the radiation efficiency was 0.72. Aftershocks were intensely triggered near the edge of large coseismic slip regions where shear stress increased. The aftershock region expanded along the fault strike, which can be attributed to the postseismic aseismic slip of the mainshock. We find that the foreshocks, mainshock, aftershocks, and postseismic slip released stress at different segments along the fault, which may reflect differences in frictional properties. Obtained results were similar to those observed for interplate earthquakes, which supports the hypothesis that the deformation processes along plate boundaries and intraplate faults are fundamentally the same.
Deficiency in the autophagy modulator Dram1 exacerbates pyroptotic cell death of Mycobacteria-infected macrophages
Authors: Zhang Rui , Varela Monica , Forn-Cuní Gabriel , Torraca Vincenzo , van der Vaart Michiel , Meijer Annemarie H.
Published: April 2020

DNA damage regulated autophagy modulator 1 (DRAM1) is a stress-inducible regulator of autophagy and cell death. DRAM1 has been implicated in cancer, myocardial infarction, and infectious diseases, but the molecular and cellular functions of this transmembrane protein remain poorly understood. Previously, we have proposed DRAM1 as a host resistance factor for tuberculosis (TB) and a potential target for host-directed anti-infective therapies. In this study, we generated a zebrafish dram1 mutant and investigated its loss-of-function effects during Mycobacterium marinum (Mm) infection, a widely used model in TB research. In agreement with previous knockdown analysis, dram1 mutation increased the susceptibility of zebrafish larvae to Mm infection. RNA sequencing revealed major effects of Dram1 deficiency on metabolic, immune response, and cell death pathways during Mm infection, and only minor effects on proteinase and metabolic pathways were found under uninfected conditions. Furthermore, unchallenged dram1 mutants did not display overt autophagic defects, but autophagic targeting of Mm was reduced in the absence of Dram1. The phagocytic ability of macrophages in dram1 mutants was unaffected, but acidification of Mm-containing vesicles was strongly reduced, indicating that Dram1 is required for phagosome maturation. By in vivo imaging, we observed that Dram1-deficient macrophages fail to restrict Mm during early stages of infection. The resulting increase in bacterial burden could be reverted by knockdown of inflammatory caspase a (caspa) and gasdermin Eb (gsdmeb), demonstrating pyroptosis as the mechanism underlying premature cell death of Mm-infected macrophages in dram1 mutants. Collectively, these data demonstrate that dissemination of mycobacterial infection in zebrafish larvae is promoted in the absence of Dram1 due to reduced maturation of mycobacteria-containing vesicles, failed intracellular containment, and consequent pyroptotic death of infected macrophages. These results provide new evidence that Dram1 plays a central role in host resistance to intracellular infection, acting at the crossroad of autophagy and cell death.
A necroptotic-independent function of MLKL in regulating endothelial cell adhesion molecule expression
Authors: Dai Jialin , Zhang Chonghe , Guo Lin , He Hao , Jiang Kai , Huang Yingying , Zhang Xixi , Zhang Haibing , Wei Wu , Zhang Yaoyang , Lu Lihua , Hu Junhao
Published: April 2020

Mixed-lineage kinase domain-like protein (MLKL) is known as the terminal executor of necroptosis. However, its function outside of necroptosis is still not clear. Herein, we demonstrate that MLKL promotes vascular inflammation by regulating the expression of adhesion molecules ICAM1, VCAM1, and E-selectin in endothelial cells (EC). MLKL deficiency suppresses the expression of these adhesion molecules, thereby reducing EC-leukocyte interaction in vitro and in vivo. Mechanistically, we show that MLKL interacts with RBM6 to promote the mRNA stability of adhesion molecules. In conclusion, this study identified a novel role of MLKL in regulating endothelial adhesion molecule expression and local EC-leukocyte interaction during acute inflammation.
CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade
Authors: Li Suting , Hao Menglei , Li Bingshu , Chen Mao , Chen Jue , Tang Jianming , Hong Shasha , Min Jie , Hu Ming , Hong Li
Published: April 2020

Multiple vaginal delivery (MVD) is an important factor for pelvic floor muscle (PFM) function decline and pelvic floor dysfunction (PFD). PFD is common in middle-aged and elderly women, but its pathogenesis is not clear. In this study, we found that the expression of CACNA1H was lower in the PFM of old mice after MVD compared with old or adult mice. In in-vitro studies, we found that treatment with the T-type Ca2+ channel (T-channel) inhibitor NNC-55 or downregulation of the CACNA1H gene by siRNA intervention promoted myotube atrophy and apoptosis. Mechanistically, we revealed that NNC-55 increased the expression of GRP78 and DDIT3 in myotubes, indicating endoplasmic reticulum stress (ERS) activation, and that the IRE1 and PERK pathways might be involved in this effect. NNC-55 induced the formation of autophagosomes but inhibited autophagy flux. Moreover, rapamycin, an autophagy activator, did not rescue myotube atrophy or apoptosis induced by NNC-55, and the autophagy inhibitors 3-MA and HCQ accelerated this damage. Further studies showed that the ERS inhibitors 4-PBA and TUDAC relieved NNC-55-induced damage and autophagy flux blockade. Finally, we found multisite muscle atrophy and decreased muscle function in Cacna1h−/− (TH-null) mice, as well as increased autophagy inhibition and apoptotic signals in the PFM of old WT mice after MVD and TH-null mice. Taken together, our results suggest that MVD-associated PFD is partially attributed to CACNA1H downregulation-induced PFM atrophy and that ERS is a potential therapeutic target for this disease.
Record thermopower found in an IrMn-based spintronic stack
Authors: Tu Sa , Ziman Timothy , Yu Guoqiang , Wan Caihua , Hu Junfeng , Wu Hao , Wang Hanchen , Liu Mengchao , Liu Chuanpu , Guo Chenyang , Zhang Jianyu , Cabero Z. Marco A. , Zhang Youguang , Gao Peng , Liu Song , Yu Dapeng , Han Xiufeng , Hallsteinsen Ingrid , Gilbert Dustin A. , Matsuo Mamoru , Ohnuma Yuichi , Wölfle Peter , Wang Kang L. , Ansermet Jean-Philippe , Maekawa Sadamichi , Yu Haiming
Published: April 2020

The Seebeck effect converts thermal gradients into electricity. As an approach to power technologies in the current Internet-of-Things era, on-chip energy harvesting is highly attractive, and to be effective, demands thin film materials with large Seebeck coefficients. In spintronics, the antiferromagnetic metal IrMn has been used as the pinning layer in magnetic tunnel junctions that form building blocks for magnetic random access memories and magnetic sensors. Spin pumping experiments revealed that IrMn Néel temperature is thickness-dependent and approaches room temperature when the layer is thin. Here, we report that the Seebeck coefficient is maximum at the Néel temperature of IrMn of 0.6 to 4.0 nm in thickness in IrMn-based half magnetic tunnel junctions. We obtain a record Seebeck coefficient 390 (±10) μV K−1 at room temperature. Our results demonstrate that IrMn-based magnetic devices could harvest the heat dissipation for magnetic sensors, thus contributing to the Power-of-Things paradigm.
Mapping the spreading routes of lymphatic metastases in human colorectal cancer
Authors: Zhang Chong , Zhang Lin , Xu Tianlei , Xue Ruidong , Yu Liang , Zhu Yuelu , Wu Yunlong , Zhang Qingqing , Li Dongdong , Shen Shuohao , Tan Dongfeng , Bai Fan , Zhang Haizeng
Published: April 2020

Lymphatic metastases are closely associated with tumor relapse and reduced survival in colorectal cancer (CRC). How tumor cells disseminate within the lymphatic network remains largely unknown. Here, we analyze the subclonal structure of 94 tumor samples, covering the primary tumors, lymph node metastases (LNMs), and liver metastases from 10 CRC patients. We portray a high-resolution lymphatic metastatic map for CRC by dividing LNMs into paracolic, intermediate, and central subgroups. Among the 61 metastatic routes identified, 38 (62.3%) are initiated from the primary tumors, 22 (36.1%) from LNMs, and 1 from liver metastasis (1.6%). In 5 patients, we find 6 LNMs that reseed 2 or more LNMs. We summarize 3 diverse modes of metastasis in CRC and show that skip spreading of tumor cells within the lymphatic network is common. Our study sheds light on the complicated metastatic pattern in CRC and has great clinical implications.
Perceptual saccadic suppression starts in the retina
Authors: Idrees Saad , Baumann Matthias P. , Franke Felix , Münch Thomas A. , Hafed Ziad M.
Published: April 2020

Visual sensitivity, probed through perceptual detectability of very brief visual stimuli, is strongly impaired around the time of rapid eye movements. This robust perceptual phenomenon, called saccadic suppression, is frequently attributed to active suppressive signals that are directly derived from eye movement commands. Here we show instead that visual-only mechanisms, activated by saccade-induced image shifts, can account for all perceptual properties of saccadic suppression that we have investigated. Such mechanisms start at, but are not necessarily exclusive to, the very first stage of visual processing in the brain, the retina. Critically, neural suppression originating in the retina outlasts perceptual suppression around the time of saccades, suggesting that extra-retinal movement-related signals, rather than causing suppression, may instead act to shorten it. Our results demonstrate a far-reaching contribution of visual processing mechanisms to perceptual saccadic suppression, starting in the retina, without the need to invoke explicit motor-based suppression commands.
Chemical modifications of adenine base editor mRNA and guide RNA expand its application scope
Authors: Jiang Tingting , Henderson Jordana M. , Coote Kevin , Cheng Yi , Valley Hillary C. , Zhang Xiao-Ou , Wang Qin , Rhym Luke H. , Cao Yueying , Newby Gregory A. , Bihler Hermann , Mense Martin , Weng Zhiping , Anderson Daniel G. , McCaffrey Anton P. , Liu David R. , Xue Wen
Published: April 2020

CRISPR-Cas9-associated base editing is a promising tool to correct pathogenic single nucleotide mutations in research or therapeutic settings. Efficient base editing requires cellular exposure to levels of base editors that can be difficult to attain in hard-to-transfect cells or in vivo. Here we engineer a chemically modified mRNA-encoded adenine base editor that mediates robust editing at various cellular genomic sites together with moderately modified guide RNA, and show its therapeutic potential in correcting pathogenic single nucleotide mutations in cell and animal models of diseases. The optimized chemical modifications of adenine base editor mRNA and guide RNA expand the applicability of CRISPR-associated gene editing tools in vitro and in vivo.
A mycorrhizae-like gene regulates stem cell and gametophore development in mosses
Authors: Wang Shuanghua , Guan Yanlong , Wang Qia , Zhao Jinjie , Sun Guiling , Hu Xiangyang , Running Mark P. , Sun Hang , Huang Jinling
Published: April 2020

Plant colonization of land has been intimately associated with mycorrhizae or mycorrhizae-like fungi. Despite the pivotal role of fungi in plant adaptation, it remains unclear whether and how gene acquisition following fungal interaction might have affected the development of land plants. Here we report a macro2 domain gene in bryophytes that is likely derived from Mucoromycota, a group that includes some mycorrhizae-like fungi found in the earliest land plants. Experimental and transcriptomic evidence suggests that this macro2 domain gene in the moss Physcomitrella patens, PpMACRO2, is important in epigenetic modification, stem cell function, cell reprogramming and other processes. Gene knockout and over-expression of PpMACRO2 significantly change the number and size of gametophores. These findings provide insights into the role of fungal association and the ancestral gene repertoire in the early evolution of land plants.
The Difficulty of Effectively Using Allocentric Prior Information in a Spatial Recall Task
Authors: Negen James , Bird Laura-Ashleigh , King Eleanor , Nardini Marko
Published: April 2020

Prior information represents the long-term statistical structure of an environment. For example, colds develop more often than throat cancer, making the former a more likely diagnosis for a sore throat. There is ample evidence for effective use of prior information during a variety of perceptual tasks, including the ability to recall locations using an egocentric (self-based) frame. However, it is not yet known if people can use prior information effectively when using an allocentric (world-based) frame. Forty-eight adults were shown sixty sets of three target locations in a sparse virtual environment with three beacons. The targets were drawn from one of four prior distributions. They were then asked to point to the targets after a delay and a change in perspective. While searches were biased towards the beacons, we did not find any evidence that participants successfully exploited the prior distributions of targets. These results suggest that allocentric reasoning does not conform to normative Bayesian models: we saw no evidence for use of priors in our cognitively-complex (allocentric) task, unlike in previous, simpler (egocentric) recall tasks. It is possible that this reflects the high biological cost of processing precise allocentric information.
Study on the relationship between hyperthyroidism and vascular endothelial cell damage
Authors: Yu Tianlong , Jing Miao , Gao Yunyan , Liu Chang , Liu Lanchun , Jia Haihan , Liu Peng , Chang Manli
Published: April 2020

The aim of the research is to explore the relationship between hyperthyroidism, iodine, antithyroid drugs (propylthiouracil) and vascular endothelial injury. In total, 136 SD rats were randomly allocated into the control group, the hyperthyroidism group, the hyperthyroidism propylthiouracil group, the hyperthyroidism low iodine group, the high iodine group, and the endothelial injury group. Rats were raised for 60 days. Afterward, indicators concerning endothelial damage were determined, including the von Willebrand Factor (vWF), thrombomodulin (TM), nitric oxide (NO), endothelin 1 (ET-1), and P-selectin, as well as the plant hemagglutinin sample type oxidized low-density lipoprotein receptor 1 (LOX-1) from the aorta and the number of endothelial progenitor cells (EPCs) in whole blood. The hyperthyroidism group had significantly higher values for vWF, TM, NO, ET-1, and P-selectin in serum and a higher number of EPCs in whole blood compared with the control group, similar to the LOX-1 expression in abdominal aorta. The hyperthyroidism low iodine group had significantly higher values for vWF, ET-1, and P-selectin in serum and a higher number of EPCs in whole blood compared with those of the control group, as was the case for LOX-1 expression in the abdominal aorta. The hyperthyroidism propylthiouracil group had significantly higher values for FT4 in the serum compared with those in the control group. The electron microscope showed that hyperthyroidism caused a certain degree of endothelial injury to the abdominal aorta in rats. Hyperthyroidism can damage the vascular endothelium and is a high-risk factor for cardio-cerebrovascular disease. Propylthiouracil could be used in the treatment of hyperthyroidism, thus protecting endothelial cells from damage.
PIBS: Proton and ion beam spectroscopy for in vivo measurements of oxygen, carbon, and calcium concentrations in the human body
Authors: Magalhaes Martins Paulo , Dal Bello Riccardo , Ackermann Benjamin , Brons Stephan , Hermann German , Kihm Thomas , Seco Joao
Published: April 2020

Proton and ion beam therapy has proven to benefit tumour control with lower side-effects, mostly in paediatrics. Here we demonstrate a feasible technique for proton and ion beam spectroscopy (PIBS) capable of determining the elemental compositions of the irradiated tissues during particle therapy. This follows the developments in prompt gamma imaging for online range verification and the inheritance from prompt gamma neutron activation analysis. Samples of water solutions were prepared to emulate varying oxygen and carbon concentrations. The irradiation of those samples and other tissue surrogate inserts by protons and ion beams under clinical conditions clearly showed a logarithmic relationship between the target elemental composition and the prompt gamma production. This finding is in line with the known logarithmic dependence of the pH with the proton molar concentration. Elemental concentration changes of 1% for calcium and 2% for oxygen in adipose, brain, breast, liver, muscle and bone-related tissue surrogates were clearly identified. Real-time in vivo measurements of oxygen, carbon and calcium concentrations will be evaluated in a pre-clinical and clinical environment. This technique should have an important impact in the assessment of tumour hypoxia over the course of several treatment fractions and the tracking of calcifications in brain metastases.
Critical behavior and magnetocaloric effect across the magnetic transition in Mn1+xFe4−xSi3
Authors: Singh Vikram , Bag Pallab , Rawat R. , Nath R.
Published: April 2020

The nature of the magnetic transition, critical scaling of magnetization, and magnetocaloric effect in Mn1+xFe4−xSi3 (x = 0 to 1) are studied in detail. Our measurements show no thermal hysteresis across the magnetic transition for the parent compound which is in contrast with the previous report and corroborate the second order nature of the transition. The magnetic transition could be tuned continuously from 328 K to 212 K with Mn substitution at the Fe site. The Mn substitution leads to a linear increase in the unit cell volume and a slight reduction in the effective moment. A detailed critical analysis of the magnetization data for x = 0.0 and 0.2 is performed in the critical regime using the modified Arrott plots, Kouvel-Fisher plot, universal curve scaling, and scaling analysis of magnetocaloric effect. The magnetization isotherms follow modified Arrott plots with critical exponent (β$$\simeq $$≃ 0.308, γ$$\simeq $$≃ 1.448, and δ$$\simeq $$≃ 5.64) for the parent compound (x = 0.0) and (β$$\simeq $$≃ 0.304, γ$$\simeq $$≃ 1.445, and δ$$\simeq $$≃ 5.64) for x = 0.2. The Kouvel-Fisher and universal scaling plots of the magnetization isotherms further confirm the reliability of our critical analysis and values of the exponents. These values of the critical exponents are found to be same for both the parent and doped samples which do not fall under any of the standard universality classes. The exchange interaction decays as J(r) ~ r−3.41 following the renormalization group theory and the observed critical exponents correspond to lattice dimensionality d = 2, spin dimensionality n = 1, and the range of interaction σ = 1.41. This value of σ(<2) indicates long-range interaction between magnetic spins. A reasonable magnetocaloric effect ΔSm$$\simeq $$≃ −6.67 J/Kg-K and −5.84 J/Kg-K for x = 0.0 and 0.2 compounds, respectively, with a huge relative cooling power (RCP ~ 700 J/Kg) for 9 T magnetic field change is observed. The universal scaling of magnetocaloric effect further mimics the second order character of the magnetic transition. The obtained critical exponents from the critical analysis of magnetocaloric effect agree with the values deduced from the magnetic isotherm analysis.
Neuroligin-1 is altered in the hippocampus of Alzheimer’s disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers
Authors: Dufort-Gervais Julien , Provost Chloé , Charbonneau Laurence , Norris Christopher M. , Calon Frédéric , Mongrain Valérie , Brouillette Jonathan
Published: April 2020

Synapse loss occurs early and correlates with cognitive decline in Alzheimer’s disease (AD). Synaptotoxicity is driven, at least in part, by amyloid-beta oligomers (Aβo), but the exact synaptic components targeted by Aβo remain to be identified. We here tested the hypotheses that the post-synaptic protein Neuroligin-1 (NLGN1) is affected early in the process of neurodegeneration in the hippocampus, and specifically by Aβo, and that it can modulate Aβo toxicity. We found that hippocampal NLGN1 was decreased in patients with AD in comparison to patients with mild cognitive impairment and control subjects. Female 3xTg-AD mice also showed a decreased NLGN1 level in the hippocampus at an early age (i.e., 4 months). We observed that chronic hippocampal Aβo injections initially increased the expression of one specific Nlgn1 transcript, which was followed by a clear decrease. Lastly, the absence of NLGN1 decreased neuronal counts in the dentate gyrus, which was not the case in wild-type animals, and worsens impairment in spatial learning following chronic hippocampal Aβo injections. Our findings support that NLGN1 is impacted early during neurodegenerative processes, and that Aβo contributes to this effect. Moreover, our results suggest that the presence of NLGN1 favors the cognitive prognosis during Aβo-driven neurodegeneration.
Cold Atmospheric Plasma Stimulates Clathrin-Dependent Endocytosis to Repair Oxidised Membrane and Enhance Uptake of Nanomaterial in Glioblastoma Multiforme Cells
Authors: He Zhonglei , Liu Kangze , Scally Laurence , Manaloto Eline , Gunes Sebnem , Ng Sing Wei , Maher Marcus , Tiwari Brijesh , Byrne Hugh J. , Bourke Paula , Tian Furong , Cullen Patrick J. , Curtin James F.
Published: April 2020

Cold atmospheric plasma (CAP) enhances uptake and accumulation of nanoparticles and promotes synergistic cytotoxicity against cancer cells. However, the mechanisms are not well understood. In this study, we investigate the enhanced uptake of theranostic nanomaterials by CAP. Numerical modelling of the uptake of gold nanoparticle into U373MG Glioblastoma multiforme (GBM) cells predicts that CAP may introduce a new uptake route. We demonstrate that cell membrane repair pathways play the main role in this stimulated new uptake route, following non-toxic doses of dielectric barrier discharge CAP. CAP treatment induces cellular membrane damage, mainly via lipid peroxidation as a result of reactive oxygen species (ROS) generation. Membranes rich in peroxidised lipids are then trafficked into cells via membrane repairing endocytosis. We confirm that the enhanced uptake of nanomaterials is clathrin-dependent using chemical inhibitors and silencing of gene expression. Therefore, CAP-stimulated membrane repair increases endocytosis and accelerates the uptake of gold nanoparticles into U373MG cells after CAP treatment. We demonstrate the utility of CAP to model membrane oxidative damage in cells and characterise a previously unreported mechanism of membrane repair to trigger nanomaterial uptake. This knowledge will underpin the development of new delivery strategies for theranostic nanoparticles into cancer cells.