bluuebunny/crossref_metadata_2025 huggingface dataset:
AXS-05 (DEXTROMETHORPHAN-BUPROPION) Improves Depressive Symptoms and Functioning in Patients With One Prior Treatment Failure: Results From the Evolve Long-Term, Open Label Study
Authors: Jones Amanda , Streicher Caroline , Alter Shawn , Thomas Zachariah , Tabuteau Herriot
Published: April 2023

Background

In STAR*D, following non-remission with an SSRI, remission rates for second-line treatments were ~ 25%, regardless of the switch strategy employed. Antidepressants with novel mechanisms may improve outcomes in MDD. AXS-05 (dextromethorphan HBr 45 mg- bupropion HCl 105 mg) is a novel, oral, investigational, NMDA receptor antagonist with multimodal activity. The dextromethorphan component of AXS-05 is an NMDA receptor antagonist and a sigma-1 receptor agonist. The bupropion component of AXS-05 serves primarily to increase the bioavailability of dextromethorphan.

Methods

EVOLVE was an open-label study, in which patients were treated with AXS-05 twice daily for up to 15 months. Subjects had either rolled in after a prior AXS-05 study or were directly enrolled and had a DSM-5 diagnosis of MDD, a MADRS score of ≥25, and had been treated with ≥1 antidepressant in the current major depressive episode (MDE). A total of 186 patients were enrolled. Here we present the results for the directly enrolled patients (n =146).

Results

Mean change in MADRS total score from a baseline of 32.2 were -9.1±7.64, -13.3±8.58, and -20.4±7.79 points at Weeks 1, 2, and 6, respectively (p< 0.001 for all). Remission (MADRS ≤10) was achieved by 5.7%, 16.2%, and 46.0% of patients at Weeks 1, 2, and 6, respectively. Improvement in functioning, measured by the SDS, was seen starting at Week 1 (p < 0.001). Improvements in MADRS and SDS were sustained at Month 12.

Long-term treatment with AXS-05 was generally well tolerated. The most commonly reported adverse events were COVID-19 infection (8.9%), nausea (8.9%), headache (7.5%), dry mouth (6.2%), insomnia (5.5%), and dizziness (5.5%).

Conclusions

AXS-05 improved depression and functioning in patients who failed one prior antidepressant in the current MDE.

Funding

Axsome Therapeutics
Efficacy and Safety of Lurasidone in a Younger Population With Bipolar Depression: Pooled Post-hoc Analysis of Two Placebo-controlled Studies
Authors: Davey Chris , Ratheesh Aswin , Tocco Michael , Mao Yongcai , George; David , Pikalov Andrei , Singh Manpreet K
Published: April 2023

Introduction

Early onset of bipolar disorder is associated with high rates of psychiatric comorbidity (e.g., anxiety disorders, ADHD, PTSD), high rates of recurrence, and marked impairment in functioning and quality of life. The aim of this analysis was to evaluate the efficacy and safety of lurasidone in bipolar depression in youth and young adult patients (10–30 years old).

Methods

Data from two 6-week, double-blind, placebo-controlled studies of lurasidone monotherapy for bipolar I depression were pooled for this analysis. In the 1st study, patients 10–17 years old were evaluated using the Children’s Depression Rating Scale–Revised (CDRS-R) and the Clinical Global Impression-Bipolar Severity (CGI-BP-S) depression scale; in the 2nd study, a subgroup of adult patients (18–30 years old) were evaluated by CGI-BP-A, and the MADRS, with the latter being converted to a CDRS-R scores using a validated conversion algorithm.

Results

The safety population consisted of 465 patients (mean age, 17.1 years; mean age of onset, 14.1; mean CDRS-R total score, 60.8). 400 patients (85.7%) completed the study. For lurasidone vs. placebo, LS mean Week 6 change was -21.4 vs. -15.3 for the CDRS-R total score (P<0.0001; ES, 0.46); and -1.6 vs. -1.1 for the CGI-BP-S score (P<0.0001; ES, 0.50). Adverse events (≥5%) on lurasidone vs. placebo were nausea (15.9% vs. 5.2%), headache (15.1% vs. 13.1%), somnolence (7.9% vs. 3.8%), vomiting (5.2% vs. 3.3%), and weight increase (5.2% vs. 2.3%). No clinically meaningful changes were observed in weight, metabolic parameters, or prolactin.

Conclusions

In this post-hoc analysis of two placebo-controlled trials, lurasidone demonstrated clinically meaningful improvement of depressive symptoms in youth and young adults with bipolar depression. Lurasidone was generally safe, well-tolerated, and associated with minimal effects on weight, metabolic parameters, and prolactin.

Funding

Servier Laboratories (Aust.) Pty. Ltd., and Sunovion Pharmaceuticals Inc.
Prevention in Practice: Improving Communication on the Benefits of Treatments for Schizophrenia
Authors: Such Pedro , Madera-McDonough Jessica , Yildirim Murat
Published: April 2023

Introduction

Antipsychotic treatment can help improve outcomes in schizophrenia by reducing the risk of relapse and psychiatric hospitalization, and increasing rates of remission and recovery, particularly when used early in the disease course. However, adherence to oral antipsychotics is often poor. Long-acting injectable (LAI) antipsychotic formulations are associated with significant improvements in treatment adherence compared with oral medications, but LAIs are not widely used in early-phase schizophrenia.

Methods

An educational training program, called “Prevention in Practice,” was developed to offer clinicians a range of innovative, web-based, patient-centered resources, including virtual role-play and educational films, that aim to improve communication between clinicians and patients and help progress care for patients with early-phase schizophrenia. The program was based on findings from the PRELAPSE study, in which clinicians received training to improve communication with patients. The PRELAPSE trial was a cluster randomized study conducted in 39 mental health centers across 19 US states. Sites were randomized to encourage treatment with the LAI aripiprazole once-monthly 400 mg (AOM 400) or to provide treatment as usual. Eligible patients had a diagnosis of schizophrenia, <5 years of lifetime antipsychotic use, and were aged 18–35 years. The objective was to evaluate whether use of the LAI delayed time to first hospitalization in early-phase schizophrenia, compared with usual care. Clinicians received training on the rationale for LAI use in early psychosis, transitioning to LAIs, and discussing LAIs with patients and families. Communication training included the principles of shared decision-making, suggested responses to frequently asked questions, and role-playing.

Results

In PRELAPSE, the sites randomized to encourage LAI treatment enrolled 234 patients and the sites randomized to usual care enrolled 255 patients. Training clinicians to improve their communication with patients made a difference—91% of patients with early-phase schizophrenia were willing to use LAI treatment at least once in the first 3 months of the study. Furthermore, the results showed that AOM 400 significantly prolonged time to first psychiatric hospitalization compared with usual care (hazard ratio: 0.56 [95% confidence interval: 0.34, 0.92]; p=0.02).

Conclusions

Offering clinicians training to improve their communication with patients, through techniques such as shared decision-making and motivational interviewing, may increase LAI use in early-phase schizophrenia. ”Prevention in Practice” is now available in in different countries and languages.

Funding

Otsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).
Rapid Antidepressant Effects and MADRS Item Improvements With AXS-05 (DEXTROMETHORPHAN-BUPROPION), an Oral NMDA Receptor Antagonist in Major Depressive Disorder: Results From Two Randomized Double-Blind, Controlled Trials
Authors: Jones Amanda , Streicher Caroline , Alter Shawn , Thomas Zachariah , Tabuteau Herriot
Published: April 2023

Background

AXS-05 (dextromethorphan-bupropion) is a novel, oral, investigational, NMDA receptor antagonist with multimodal activity being developed for MDD. The dextromethorphan component of AXS-05 is an NMDA receptor antagonist and a sigma-1 receptor agonist. The bupropion component of AXS-05 serves primarily to increase the bioavailability of dextromethorphan.

Methods

AXS-05 was evaluated in two double-blind, randomized, controlled, 6-week trials. The GEMINI trial (N=327) was placebo-controlled and the ASCEND trial (N=80) used bupropion as the control. Here we focus on efficacy in the first 2 weeks of treatment and present a pooled analysis of the individual items of the MADRS for AXS-05 as compared to control.

Results

In GEMINI, starting at Week 1, AXS 05 was superior (p < 0.05) to placebo on: mean MADRS improvement (7.3 vs. 4.9), MADRS response (15% vs. 7%), CGI-I (22% vs. 13%), CGI-S (0.7 vs. 0.4) and Q-LES-Q-SF (9.0% vs. 5.8%). At Week 2, AXS-05 was also statistically superior to placebo on MADRS remission (17% vs.8%) and on the SDS (6.8 vs. 4.5).

In ASCEND, from Week 2, AXS-05 was superior (p< 0.05) to bupropion on: mean MADRS improvement (12.5vs. 7.8), MADRS remission (26% vs. 3%), and CGI-S (1.41 vs. 0.9).

At Week 1, treatment with AXS-05 resulted in greater improvements (p< 0.05) in reported sadness, inner tension, inability to feel, pessimistic thoughts, and suicidal thoughts, as compared to control. At Week 6, AXS-05 demonstrated significant improvements over control on seven of the ten MADRS items.

In the GEMINI trial, the most commonly reported adverse events were dizziness, nausea, headache, diarrhea, somnolence, and dry mouth.

Conclusions

Treatment with AXS-05 resulted in rapid and broad antidepressant efficacy.

Funding

Axsome Therapeutics
Targeting lncRNA NEAT1 Impedes Alzheimer’s Disease Progression via MicroRNA-193a Mediated CREB/BDNF and NRF2/NQO1 Pathways
Authors: Li Yuanlong
Published: April 2023

Background

Long noncoding RNA nuclear-enriched abundant transcript 1 (lnc-NEAT1) is closely implicated in neurological or degenerative diseases, while its implication in AD is rarely reported. This study aimed to investigate the effect of lnc-NEAT1 knockdown on neuron injury, inflammation, and oxidative stress in AD, as well as its interaction with downstream targets and pathways.

Methods

APPswe/PS1dE9 transgenic mice were injected with negative control or lnc-NEAT1 interference lentivirus. Besides, AD cellular model was constructed by amyloid β treatment in mice primary neuron cells; then, knockdown of lnc-NEAT1 and microRNA-193a (miR-193a) was performed alone or in combination.

Results

In vivo experiments revealed that Lnc-NEAT1 knockdown improved cognition in AD mice reflected by Morrison water maze and Y-maze assays. Besides, lnc-NEAT1 knockdown reduced injury and apoptosis, decreased TNF-α and IL-1β levels (indicating lower inflammation level), repressed ROS, MDA but promoted ATP and SOD levels (suggesting lower oxidative stress level), and activated CREB/BDNF and NRF2/NQO1 pathways in hippocampi of AD mice. Notably, lnc-NEAT1 down-regulated miR-193a both in vitro and in vivo; also, it acted as a decoy of miR-193a. In vitro experiments showed that lnc-NEAT1 knockdown decreased apoptosis and oxidative stress, improved cell viability, and also activated CREB/BDNF and NRF2/NQO1 pathways in AD cellular model. Meanwhile, miR-193a knockdown showed the opposite effects, which also attenuated lnc-NEAT1 knockdown-mediated reduction in injury, oxidative stress, and activation of CREB/BDNF and NRF2/NQO1 pathways of AD cellular model.

Conclusion

Lnc-NEAT1 knockdown reduces neuron injury, inflammation, and oxidative stress through activating miR-193a mediated CREB/BDNF and NRF2/NQO1 pathways in AD.

Funding

No Funding
It’s complicated: Executive functioning moderates impacts of daily busyness on everyday functioning in community-dwelling older adults
Authors: Suchy Yana , Gereau Mora Michelle , DesRuisseaux Libby A. , Brothers Stacey L.
Published: April 2023

Objective:

Research shows that cognitively healthy older adults with mild executive function (EF) weaknesses are vulnerable to the negative impacts of life complexity (or daily busyness) when performing instrumental activities of daily living (IADLs). However, past research assessed life complexity only at one timepoint, not capturing daily fluctuations. Importantly, fluctuations in busyness can themselves have deleterious impacts on functioning. This study extended past research by examining whether (1) variability in daily busyness would be more detrimental than level of busyness to performance of IADLs, and (2) EF assessed at home would moderate deleterious impact of busyness on IADLs.

Method:

Fifty-two community-dwelling older adults aged 60 to 95 completed daily IADL tasks and daily measures of EF and busyness via ecological momentary assessment, independently at home for 18 days.

Results:

(1) In a subset of participants with mild EF weaknesses, high variability in busyness across days was associated with fewer tasks completed correctly; and (2) across all participants (regardless of EF), high levels of daily busyness were associated with fewer tasks completed on time.

Conclusions:

Findings indicate that high variability in daily busyness, potentially reflecting a lack of daily routine, was associated with IADL errors among cognitively healthy older adults with mild EF weaknesses. Additionally, consistently high levels of busyness were associated with failures to complete tasks, or failures to complete them on time, regardless of EF. These results further support the Contextually Valid Executive Assessment (ConVExA) model, which posits that EF and contextual factors interact to predict functional outcomes.
The Emergence of the Romanian National School of Composition in the First Half of the Nineteenth Century: Between the Western Canon and the Resources of the Local Music
Authors: Constantiniu Theodor
Published: April 2023

This article aims to explain the rise of Western art forms in the musical creation of the Romanian Principalities in the first half of the nineteenth century, as dictated by a particular European political and economic dynamic. I analyse the spread of Western music – usually described as a consequence of the gradual modernization of Romanian society – in terms of the power relations between the European core and a newly integrated periphery at the Eastern border of the continent. To illustrate this change, I discuss Edward Said's concept of orientalism which helps describe the early interactions between Western musicians and professionals and the local music traditions and customs. I then show how these interactions gave the former access to a distinctive musical material used in compositions targeting an expanding European music market. In an age of national struggle in the Romanian Principalities, national music was both a concept and a practice in demand by the local intelligentsia and fostered by composers. However, in addition to this agreement, the concept of national music signalled some significant societal changes that I elucidate by looking at class stratification and the evolution of musical taste. In the final part of the analysis, I draw on dependency theory authors such as Samir Amin and Daniel Chirot to argue that musical life in the first half of the nineteenth century in Wallachia and Moldavia was closely mirroring the economic development of these countries. Thus, I demonstrate that the emergence of the Romanian school of composition must be understood not only at a national level but also within a broader political, economic and social context, defined by the gradual transition to capitalist modes of production and consumption that happened in the first decades of the nineteenth century.
A ConvLSTM‐Based Prediction Model of Aurora Evolution During the Substorm Expansion Phase
Authors: Jiang Jianan , Zou Ziming , Lu Yang
Published: April 2023

Aurora is an important manifestation of solar‐terrestrial physical processes. The aurora activities have rapid changes in spatial and intensity distribution during a substorm, especially the expansion phase. In this paper, a newly developed aurora evolution model is built based on the Convolutional Long Short‐Term Memory network, using the aurora images captured by the ultraviolet imager on the Polar satellite during the substorm expansion phases. Given the images after the onset, the model can predict the evolution of aurora with reasonable accuracy. The structure similarity, Peak Signal‐to‐Noise Ratio (Peak Signal to Noise Ratio), and Root Mean Square Error are used to evaluate the similarity between the predicted and observed images. The results demonstrate that the model performs well at different scales of evolution. Additionally, the model can estimate the evolution of both the aurora intensities and the movement of the poleward boundary. Furthermore, three cases are displayed to illustrate the behavior of the model and its limitation.
Discovery of a New Inter‐Basin Climate Pattern: Australia Boundary Current Dipole
Authors: Han Jie‐Hong , Li Jianping
Published: April 2023

A new inter‐basin teleconnection analysis method is proposed to comprehensively investigate the connection among global oceans. The strong negative correlation (−0.59) between sea surface temperature (SST) along Leeuwin Current (LC) and East Australia Current (EAC) is discovered and named as Australia Boundary Current Dipole (ABCD). This new inter‐basin air‐sea coupled mode exhibits remarkable interannual variability, with a peak phase in austral summer. The related SST anomalies are mainly generated by anomalous Australia High induced opposite alongshore surface winds to enhance/suppress the heat transport of the two warm currents, in turn, reinforce the wind anomalies by heating/cooling the overlying atmosphere and changing regional pressure anomalies. The meridional ocean advections control the anomalous SST, indicating the essential role of coastal Bjerknes feedback. The kinetic energy analysis further demonstrates that ABCD represents the reverse variation pattern of LC and EAC.
Induced Earthquake Source Parameters, Attenuation, and Site Effects From Waveform Envelopes in the Fennoscandian Shield
Authors: Eulenfeld Tom , Hillers Gregor , Vuorinen Tommi A. T. , Wegler Ulrich
Published: April 2023

We analyze envelopes of 233 and 22 ML0.0 to ML1.8 earthquakes induced by two geothermal stimulations in the Helsinki, Finland, metropolitan area. We separate source spectra and site terms and determine intrinsic attenuation and the scattering strength of shear waves in the 3–200 Hz frequency range using radiative transfer based synthetic envelopes. Displacement spectra yield scaling relations with a general deviation from self‐similarity, with a stronger albeit more controversial signal from the weaker 2020 stimulation. The 2020 earthquakes also tend to have a smaller local magnitude compared to 2018 earthquakes with the same moment magnitude. We discuss these connections in the context of fluid effects on rupture speed or medium properties. Site terms demonstrate that the spectral amplification relative to two reference borehole sites is not neutral at the other sensors; largest variations are observed at surface stations at frequencies larger than 30 Hz. Intrinsic attenuation is exceptionally low with values down to 2.4 × 10−5 at 20 Hz, which allows the observation of a diffuse reflection at the ∼50 km deep Moho. Scattering strength is in the range of globally observed data with between 10−3 and 10−4. The application of the employed Qopen analysis program to the 2020 data in a retrospective monitoring mode demonstrates its versatility as a seismicity processing tool. The diverse results have implications for scaling relations, hazard assessment and ground motion modeling, and imaging and monitoring using ballistic and scattered wavefields in the crystalline Fennoscandian Shield environment.
Semicentennial Response of a Bifurcation Region in an Engineered River to Peak Flows and Human Interventions
Authors: Chowdhury M. Kifayath , Blom Astrid , Ylla Arbós Clàudia , Verbeek Merel C. , Schropp Max H. I. , Schielen Ralph M. J.
Published: April 2023

A bifurcation in an engineered river system (i.e., fixed planform and width) has fewer degrees of freedom in its response to interventions and natural changes than a natural bifurcation system. Our objective is to provide insight into how a bifurcation in an engineered river responds to peak flows and human interventions. To this end, we analyze the change in hydraulics, bed level, and bed surface grain size in the region of two bifurcations in the upper Rhine delta in the Netherlands over the last century. We show that, over the last two decades, the water discharge in one bifurcate (the Waal branch) has steadily increased at the expense of the other. This gradual increase in the water discharge of the first branch is associated with its erosion rate being larger than the other branch. The quick succession of two or three peak flow events (1993, 1995, and 1998) caused rapid sediment deposition over the upstream part of the bifurcate that has gradually lost discharge, which seems to have triggered the slow change in flow partitioning.
Hydroclimate Drives Seasonal Riverine Export Across a Gradient of Glacierized High‐Latitude Coastal Catchments
Authors: Jenckes J. , Munk L. A. , Ibarra D. E. , Boutt D. F. , Fellman J. , Hood E.
Published: April 2023

Glacierized coastal catchments of the Gulf of Alaska (GoA) are undergoing rapid hydrologic fluctuations in response to climate change. These catchments deliver dissolved and suspended inorganic and organic matter to nearshore marine environments, however, these glacierized coastal catchments are relatively understudied and little is known about total solute and particulate fluxes to the ocean. We present hydrologic, physical, and geochemical data collected during April–October 2019–2021 from 10 streams along gradients of glacial fed to non‐glacial (i.e., precipitation) fed, in one Southcentral and one Southeast Alaska region. Hydrologic data reveal that glaciers drive the seasonal runoff patterns. The ẟ18O signature and specific conductance show distinctive seasonal variations in stream water sources between the study regions apparently due to the large amounts of rain in Southeast Alaska. Total dissolved solids concentrations and yields were elevated in the Southcentral region, due to lithologic influence on dissolved loads, however, the hydroclimate is the primary driver of the timing of dissolved and suspended yields. We show the yields of dissolved organic carbon is higher and that the δ13CPOC is enriched in the Southeast streams illustrating contrasts in organic carbon export across the GoA. Finally, we illustrate how future yields of solutes and sediments to the GoA may change as watersheds evolve from glacial influenced to precipitation dominated. This integrated analysis provides insights into how watershed characteristics beyond glacier coverage control properties of freshwater inputs to the GoA and the importance of expanding study regions to multiple hydroclimate regimes.
The prevalence and profile of spinal cord injury in public healthcare rehabilitation units in Gauteng, South Africa
Authors: Alves Michael Alexandre , Pilusa Sonti , Mashola Mokgadi Kholofelo
Published: April 2023

Study design

Retrospective medical record review.

Objective

To determine the prevalence and describe the profile of person with SCI (PWSCI) admitted in the public healthcare sector in Gauteng, South Africa.

Setting

Specialized public healthcare rehabilitation units in Gauteng, South Africa.

Methods

Medical records of PWSCI admitted to public healthcare rehabilitation units between 01 January 2018 and 31 December 2019 were perused. Data were collected anonymously and then summarised using descriptive and inferential statistics. Significance was set at p < 0.05.

Results

386 of 998 participants (38.7%) were admitted following SCI and the mean age was 36.9 years. Most participants were male (69.9%), with females significantly more likely to sustain a NTSCI (p < 0.001), which was the least common cause of SCI (34.9%). Those sustaining a TSCI were found to be significantly younger than their NTSCI counterparts (p < 0.001). Assault was the leading cause of injury (35.2%), and a positive HIV status with the presence of comorbidities were found to be significant risk factors for developing a NTSCI (p < 0.001). Most injuries were between T7-T12 (39.9%) and were complete (56.9%). The rehabilitation length of stay 85.6 days, with a mortality rate of 6.48%.

Conclusions

Gauteng has among the highest global proportion of TSCI due to assault. Of interest, more females sustained a NTSCI than their male counterparts. There is a need to strengthen SCI prevention strategies, particularly targeting assault in young males and infectious causes in females and older populations. Further epidemiological and outcomes-based research is required for PWSCI.
Expression of macromolecular organic nitrogen degrading enzymes identifies potential mediators of soil organic N availability to an annual grass
Authors: Sieradzki Ella T , Nuccio Erin E , Pett-Ridge Jennifer , Firestone Mary K
Published: April 2023

Nitrogen (N) is frequently limiting to plant growth, in part because most soil N is present as polymeric organic compounds that are not readily taken up by plants. Microbial depolymerization of these large macromolecular N-substrates gradually releases available inorganic N. While many studies have researched and modeled controls on soil organic matter formation and bulk N mineralization, the ecological—spatial, temporal and phylogenetic—patterns underlying organic N degradation remain unclear. We analyzed 48 time-resolved metatranscriptomes and quantified N-depolymerization gene expression to resolve differential expression by soil habitat and time in specific taxonomic groups and gene-based guilds. We observed much higher expression of extracellular serine-type proteases than other extracellular N-degrading enzymes, with protease expression of predatory bacteria declining with time and other taxonomic patterns driven by the presence (Gammaproteobacteria) or absence (Thermoproteota) of live roots and root detritus (Deltaproteobacteria and Fungi). The primary chitinase chit1 gene was more highly expressed by eukaryotes near root detritus, suggesting predation of fungi. In some lineages, increased gene expression over time suggests increased competitiveness with rhizosphere age (Chloroflexi). Phylotypes from some genera had protease expression patterns that could benefit plant N nutrition, for example, we identified a Janthinobacterium phylotype and two Burkholderiales that depolymerize organic N near young roots and a Rhizobacter with elevated protease levels near mature roots. These taxon-resolved gene expression results provide an ecological read-out of microbial interactions and controls on N dynamics in specific soil microhabitats and could be used to target potential plant N bioaugmentation strategies.
CEBPD is a master transcriptional factor for hypoxia regulated proteins in glioblastoma and augments hypoxia induced invasion through extracellular matrix-integrin mediated EGFR/PI3K pathway
Authors: Mao Xing-gang , Xue Xiao-yan , Lv Rui , Ji Ang , Shi Ting-yu , Chen Xiao-yan , Jiang Xiao-fan , Zhang Xiang
Published: April 2023

Hypoxia contributes to the initiation and progression of glioblastoma by regulating a cohort of genes called hypoxia-regulated genes (HRGs) which form a complex molecular interacting network (HRG-MINW). Transcription factors (TFs) often play central roles for MINW. The key TFs for hypoxia induced reactions were explored using proteomic analysis to identify a set of hypoxia-regulated proteins (HRPs) in GBM cells. Next, systematic TF analysis identified CEBPD as a top TF that regulates the greatest number of HRPs and HRGs. Clinical sample and public database analysis revealed that CEBPD is significantly up-regulated in GBM, high levels of CEBPD predict poor prognosis. In addition, CEBPD is highly expressed in hypoxic condition both in GBM tissue and cell lines. For molecular mechanisms, HIF1α and HIF2α can activate the CEBPD promotor. In vitro and in vivo experiments demonstrated that CEBPD knockdown impaired the invasion and growth capacity of GBM cells, especially in hypoxia condition. Next, proteomic analysis identified that CEBPD target proteins are mainly involved in the EGFR/PI3K pathway and extracellular matrix (ECM) functions. WB assays revealed that CEBPD significantly positively regulated EGFR/PI3K pathway. Chromatin immunoprecipitation (ChIP) qPCR/Seq analysis and Luciferase reporter assay demonstrated that CEBPD binds and activates the promotor of a key ECM protein FN1 (fibronectin). In addition, the interactions of FN1 and its integrin receptors are necessary for CEBPD-induced EGFR/PI3K activation by promoting EGFR phosphorylation. Furthermore, GBM sample analysis in the database corroborated that CEBPD is positively correlated with the pathway activities of EGFR/PI3K and HIF1α, especially in highly hypoxic samples. At last, HRPs are also enriched in ECM proteins, indicating that ECM activities are important components of hypoxia induced responses in GBM. In conclusion, CEPBD plays important regulatory roles in the GBM HRG-MINW as a key TF, which activates the EGFR/PI3K pathway through ECM, especially FN1, mediated EGFR phosphorylation.
Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death
Authors: Woodley Keith , Dillingh Laura S. , Giotopoulos George , Madrigal Pedro , Rattigan Kevin M. , Philippe Céline , Dembitz Vilma , Magee Aoife M. S. , Asby Ryan , van de Lagemaat Louie N. , Mapperley Christopher , James Sophie C. , Prehn Jochen H. M. , Tzelepis Konstantinos , Rouault-Pierre Kevin , Vassiliou George S. , Kranc Kamil R. , Helgason G. Vignir , Huntly Brian J. P. , Gallipoli Paolo
Published: April 2023

Resistance to standard and novel therapies remains the main obstacle to cure in acute myeloid leukaemia (AML) and is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), the first enzyme in the mannose metabolism pathway, as a sensitizer to both cytarabine and FLT3 inhibitors across multiple AML models. Mechanistically, we identify a connection between mannose metabolism and fatty acid metabolism, that is mediated via preferential activation of the ATF6 arm of the unfolded protein response (UPR). This in turn leads to cellular accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. Our findings provide further support to the role of rewired metabolism in AML therapy resistance, unveil a connection between two apparently independent metabolic pathways and support further efforts to achieve eradication of therapy-resistant AML cells by sensitizing them to ferroptotic cell death.
IDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart
Authors: Nanadikar Maithily S. , Vergel Leon Ana M. , Guo Jia , van Belle Gijsbert J. , Jatho Aline , Philip Elvina S. , Brandner Astrid F. , Böckmann Rainer A. , Shi Runzhu , Zieseniss Anke , Siemssen Carla M. , Dettmer Katja , Brodesser Susanne , Schmidtendorf Marlen , Lee Jingyun , Wu Hanzhi , Furdui Cristina M. , Brandenburg Sören , Burgoyne Joseph R. , Bogeski Ivan , Riemer Jan , Chowdhury Arpita , Rehling Peter , Bruegmann Tobias , Belousov Vsevolod V. , Katschinski Dörthe M.
Published: April 2023

Redox signaling and cardiac function are tightly linked. However, it is largely unknown which protein targets are affected by hydrogen peroxide (H2O2) in cardiomyocytes that underly impaired inotropic effects during oxidative stress. Here, we combine a chemogenetic mouse model (HyPer-DAO mice) and a redox-proteomics approach to identify redox sensitive proteins. Using the HyPer-DAO mice, we demonstrate that increased endogenous production of H2O2 in cardiomyocytes leads to a reversible impairment of cardiac contractility in vivo. Notably, we identify the γ-subunit of the TCA cycle enzyme isocitrate dehydrogenase (IDH)3 as a redox switch, linking its modification to altered mitochondrial metabolism. Using microsecond molecular dynamics simulations and experiments using cysteine-gene-edited cells reveal that IDH3γ Cys148 and 284 are critically involved in the H2O2-dependent regulation of IDH3 activity. Our findings provide an unexpected mechanism by which mitochondrial metabolism can be modulated through redox signaling processes.
Unconventional correlated insulator in CrOCl-interfaced Bernal bilayer graphene
Authors: Yang Kaining , Gao Xiang , Wang Yaning , Zhang Tongyao , Gao Yuchen , Lu Xin , Zhang Shihao , Liu Jianpeng , Gu Pingfan , Luo Zhaoping , Zheng Runjie , Cao Shimin , Wang Hanwen , Sun Xingdan , Watanabe Kenji , Taniguchi Takashi , Li Xiuyan , Zhang Jing , Dai Xi , Chen Jian-Hao , Ye Yu , Han Zheng
Published: April 2023

The realization of graphene gapped states with large on/off ratios over wide doping ranges remains challenging. Here, we investigate heterostructures based on Bernal-stacked bilayer graphene (BLG) atop few-layered CrOCl, exhibiting an over-1-GΩ-resistance insulating state in a widely accessible gate voltage range. The insulating state could be switched into a metallic state with an on/off ratio up to 107by applying an in-plane electric field, heating, or gating. We tentatively associate the observed behavior to the formation of a surface state in CrOCl under vertical electric fields, promoting electron–electron (e–e) interactions in BLG via long-range Coulomb coupling. Consequently, at the charge neutrality point, a crossover from single particle insulating behavior to an unconventional correlated insulator is enabled, below an onset temperature. We demonstrate the application of the insulating state for the realization of a logic inverter operating at low temperatures. Our findings pave the way for future engineering of quantum electronic states based on interfacial charge coupling.
Nirmatrelvir-resistant SARS-CoV-2 is efficiently transmitted in female Syrian hamsters and retains partial susceptibility to treatment
Authors: Abdelnabi Rana , Jochmans Dirk , Donckers Kim , Trüeb Bettina , Ebert Nadine , Weynand Birgit , Thiel Volker , Neyts Johan
Published: April 2023

The SARS-CoV-2 main protease (3CLpro) is one of the promising therapeutic targets for the treatment of COVID-19. Nirmatrelvir is the first 3CLpro inhibitor authorized for treatment of COVID-19 patients at high risk of hospitalization. We recently reported on the in vitro selection of SARS-CoV-2 3CLpro resistant virus (L50F-E166A-L167F; 3CLprores) that is cross-resistant with nirmatrelvir and other 3CLpro inhibitors. Here, we demonstrate that the 3CLprores virus replicates efficiently in the lungs of intranasally infected female Syrian hamsters and causes lung pathology comparable to that caused by the WT virus. Moreover, hamsters infected with 3CLprores virus transmit the virus efficiently to co-housed non-infected contact hamsters. Importantly, at a dose of 200 mg/kg (BID) of nirmatrelvir, the compound was still able to reduce the lung infectious virus titers of 3CLprores-infected hamsters by 1.4 log10 with a modest improvement in the lung histopathology as compared to the vehicle control. Fortunately, resistance to Nirmatrelvir does not readily develop in clinical setting. Yet, as we demonstrate, in case drug-resistant viruses emerge, they may spread easily which may thus impact therapeutic options. Therefore, the use of 3CLpro inhibitors in combination with other drugs may be considered, especially in immunodeficient patients, to avoid the development of drug-resistant viruses.
Drivers of SARS-CoV-2 testing behaviour: a modelling study using nationwide testing data in England
Authors: Kim Younjung , Donnelly Christl A. , Nouvellet Pierre
Published: April 2023

During the COVID-19 pandemic, national testing programmes were conducted worldwide on unprecedented scales. While testing behaviour is generally recognised as dynamic and complex, current literature demonstrating and quantifying such relationships is scarce, despite its importance for infectious disease surveillance and control. Here, we characterise the impacts of SARS-CoV-2 transmission, disease susceptibility/severity, risk perception, and public health measures on SARS-CoV-2 PCR testing behaviour in England over 20 months of the pandemic, by linking testing trends to underlying epidemic trends and contextual meta-data within a systematic conceptual framework. The best-fitting model describing SARS-CoV-2 PCR testing behaviour explained close to 80% of the total deviance in NHS test data. Testing behaviour showed complex associations with factors reflecting transmission level, disease susceptibility/severity (e.g. age, dominant variant, and vaccination), public health measures (e.g. testing strategies and lockdown), and associated changes in risk perception, varying throughout the pandemic and differing between infected and non-infected people.
Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development
Authors: Lismer Ariane , Kimmins Sarah
Published: April 2023

Although more studies are demonstrating that a father’s environment can influence child health and disease, the molecular mechanisms underlying non-genetic inheritance remain unclear. It was previously thought that sperm exclusively contributed its genome to the egg. More recently, association studies have shown that various environmental exposures including poor diet, toxicants, and stress, perturbed epigenetic marks in sperm at important reproductive and developmental loci that were associated with offspring phenotypes. The molecular and cellular routes that underlie how epigenetic marks are transmitted at fertilization, to resist epigenetic reprogramming in the embryo, and drive phenotypic changes are only now beginning to be unraveled. Here, we provide an overview of the state of the field of intergenerational paternal epigenetic inheritance in mammals and present new insights into the relationship between embryo development and the three pillars of epigenetic inheritance: chromatin, DNA methylation, and non-coding RNAs. We evaluate compelling evidence of sperm-mediated transmission and retention of paternal epigenetic marks in the embryo. Using landmark examples, we discuss how sperm-inherited regions may escape reprogramming to impact development via mechanisms that implicate transcription factors, chromatin organization, and transposable elements. Finally, we link paternally transmitted epigenetic marks to functional changes in the pre- and post-implantation embryo. Understanding how sperm-inherited epigenetic factors influence embryo development will permit a greater understanding related to the developmental origins of health and disease.
Electrosynthesis of polymer-grade ethylene via acetylene semihydrogenation over undercoordinated Cu nanodots
Authors: Xue Weiqing , Liu Xinyan , Liu Chunxiao , Zhang Xinyan , Li Jiawei , Yang Zhengwu , Cui Peixin , Peng Hong-Jie , Jiang Qiu , Li Hongliang , Xu Pengping , Zheng Tingting , Xia Chuan , Zeng Jie
Published: April 2023

The removal of acetylene impurities remains important yet challenging to the ethylene downstream industry. Current thermocatalytic semihydrogenation processes require high temperature and excess hydrogen to guarantee complete acetylene conversion. For this reason, renewable electricity-based electrocatalytic semihydrogenation of acetylene over Cu-based catalysts is an attractive route compared to the energy-intensive thermocatalytic processes. However, active Cu electrocatalysts still face competition from side reactions and often require high overpotentials. Here, we present an undercoordinated Cu nanodots catalyst with an onset potential of −0.15 V versus reversible hydrogen electrode that can exclusively convert C2H2 to C2H4 with a maximum Faradaic efficiency of ~95.9% and high intrinsic activity in excess of −450 mA cm−2 under pure C2H2 flow. Subsequently, we successfully demonstrate simulated crude ethylene purification, continuously producing polymer-grade C2H4 with <1 ppm C2H2 for 130 h at a space velocity of 1.35 × 105 ml gcat−1 h−1. Theoretical calculations and in situ spectroscopies reveal a lower energy barrier for acetylene semihydrogenation over undercoordinated Cu sites than nondefective Cu surface, resulting in the excellent C2H2-to-C2H4 catalytic activity of Cu nanodots.
Biodeterioration of pre-treated polypropylene by Aspergillus terreus and Engyodontium album
Authors: Samat Amira Farzana , Carter Dee , Abbas Ali
Published: April 2023

Polypropylene (PP) has raised severe environmental issues concerning its non-degradability, with a current recycling rate of only 1%. This current study utilisesAspergillus terreusATCC 20542 andEngyodontium albumBRIP 61534a to break down PP while focusing on pre-treatment. Polypropylene granule (GPP), film (FPP) and metallised film (MFPP) are pre-treated by either UV, heat, or Fenton’s reagent. UV and heat-treated MFPP byA. terreusexhibits notable weight loss percentage (25.29% and 22.13%, respectively). Biomass production, reduction rate, Fourier transform infrared (FTIR), and scanning electron microscopy (SEM) analyses further validate the degradation rate.A. terreusincubated with UV-treated MFPP produced a relatively high biomass yield of 1.07 mg/ml. Reduction in carbonyl index and surface morphological changes reveal consistent biodeterioration evidence. This investigation demonstrates thatA. terreusandE. albumcan grow on, change, and utilise PP as a carbon source with pre-treatments’ aid, promoting the biological pathways for plastic waste treatment.
A peptide-centric quantitative proteomics dataset for the phenotypic assessment of Alzheimer’s disease
Authors: Merrihew Gennifer E. , Park Jea , Plubell Deanna , Searle Brian C. , Keene C. Dirk , Larson Eric B. , Bateman Randall , Perrin Richard J. , Chhatwal Jasmeer P. , Farlow Martin R. , McLean Catriona A. , Ghetti Bernardino , Newell Kathy L. , Frosch Matthew P. , Montine Thomas J. , MacCoss Michael J.
Published: April 2023

Alzheimer’s disease (AD) is a looming public health disaster with limited interventions. Alzheimer’s is a complex disease that can present with or without causative mutations and can be accompanied by a range of age-related comorbidities. This diverse presentation makes it difficult to study molecular changes specific to AD. To better understand the molecular signatures of disease we constructed a unique human brain sample cohort inclusive of autosomal dominant AD dementia (ADD), sporadic ADD, and those without dementia but with high AD histopathologic burden, and cognitively normal individuals with no/minimal AD histopathologic burden. All samples are clinically well characterized, and brain tissue was preserved postmortem by rapid autopsy. Samples from four brain regions were processed and analyzed by data-independent acquisition LC-MS/MS. Here we present a high-quality quantitative dataset at the peptide and protein level for each brain region. Multiple internal and external control strategies were included in this experiment to ensure data quality. All data are deposited in the ProteomeXchange repositories and available from each step of our processing.
Open science and data sharing in cognitive neuroscience with MouseBytes and MouseBytes+
Authors: Memar Sara , Jiang Eric , Prado Vania F. , Saksida Lisa M. , Bussey Timothy J. , Prado Marco A. M.
Published: April 2023

Open access to rodent cognitive data has lagged behind the rapid generation of large open-access datasets in other areas of neuroscience, such as neuroimaging and genomics. One contributing factor has been the absence of uniform standardization in experiments and data output, an issue that has particularly plagued studies in animal models. Touchscreen-automated cognitive testing of animal models allows standardized outputs that are compatible with open-access sharing. Touchscreen datasets can be combined with different neuro-technologies such as fiber photometry, miniscopes, optogenetics, and MRI to evaluate the relationship between neural activity and behavior. Here we describe a platform that allows deposition of these data into an open-access repository. This platform, called MouseBytes, is a web-based repository that enables researchers to store, share, visualize, and analyze cognitive data. Here we present the architecture, structure, and the essential infrastructure behind MouseBytes. In addition, we describe MouseBytes+, a database that allows data from complementary neuro-technologies such as imaging and photometry to be easily integrated with behavioral data in MouseBytes to support multi-modal behavioral analysis.
Quantitative analysis of lacewing larvae over more than 100 million years reveals a complex pattern of loss of morphological diversity
Authors: Haug Carolin , Braig Florian , Haug Joachim T.
Published: April 2023

Loss of biodiversity and especially insect decline are widely recognised in modern ecosystems. This decline has an enormous impact due to the crucial ecological roles of insects as well as their economic relevance. For comparison, the fossil record can provide important insights on past biodiversity losses. One group of insects, for which a significant decline over the last 100 million years has often been postulated, but not demonstrated quantitatively, is Neuroptera (lacewings). Many adult lacewings are pollinators, while the larvae are mostly predators, which becomes very obvious from their prominent stylet-like mouthparts. We investigated the fossil record of larvae of all neuropteran lineages as well as a large share of extant neuropteran larvae. Based on these, we performed an outline analysis of the head with stylets. This analysis provides a quantitative frame for recognising the decline of lacewings since the Cretaceous, indicating also a severe loss of ecological roles.
Design and validation of Dolosigranulum pigrum specific PCR primers using the bacterial core genome
Authors: Aziz Maliha , Palmer Amber , Iversen Søren , Salazar Juan E. , Pham Tony , Roach Kelsey , Becker Karsten , Kaspar Ursula , Price Lance B. , Baig Sharmin , Stegger Marc , Andersen Paal Skytt , Liu Cindy M.
Published: April 2023

Dolosigranulum pigrum—a lactic acid bacterium that is increasingly recognized as an important member of the nasal microbiome. Currently, there are limited rapid and low-cost options for confirming D. pigrum isolates and detecting D. pigrum in clinical specimens. Here we describe the design and validation of a novel PCR assay targeting D. pigrum that is both sensitive and specific. We designed a PCR assay targeting murJ, a single-copy core species gene identified through the analysis of 21 D. pigrum whole genome sequences. The assay achieved 100% sensitivity and 100% specificity against D. pigrum and diverse bacterial isolates and an overall 91.1% sensitivity and 100% specificity using nasal swabs, detecting D. pigrum at a threshold of 1.0 × 104D. pigrum 16S rRNA gene copies per swab. This assay adds a reliable and rapid D. pigrum detection tool to the microbiome researcher toolkit investigating the role of generalist and specialist bacteria in the nasal environment.