bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial distribution of multielements including lanthanides in sediments of Iron Gate I Reservoir in the Danube River
Authors: Culicov Otilia Ana , Trtić-Petrović Tatjana , Balvanović Roman , Petković Anđelka , Ražić Slavica
Published: April 2021

Recent studies show that lanthanides (Ln) are becoming emerging pollutants due to their wide application in new technologies, but their environmental fate, transport, and possible accumulation are still relatively unknown. This study aims to determine major and trace elements including Ln in the Danube River sediment which either belong or close to the Iron Gate Reservoir. The Iron Gate Reservoir is characterized by accumulation of sediments as an effect of building hydropower dam Iron Gate I. The surface sediments were collected on the Danube River—1141 to 864 km and three tributaries along this waterway. Two samples of deep sediments were used for comparison. The results indicate the significant upward enrichment of Zn, Sb, Cr, Nd, and Dy in sediments belongs to the Iron Gate Reservoir. The sample 4-Smed is labelled as a hot spot of contamination with Zn, Cr, As, Sb, Nd, and Dy. Also, a trend of increasing concentration in the time period from 1995 to 2016 was found for elements Zn, Cr, and Ni in sediment samples in the Iron Gate Reservoir. Chemometric analysis shows the grouping of sample sites into clusters characterized by the following properties: (i) increased concentration of all measured elements (samples within the Iron Gate Reservoir); (ii) increased Cu concentration (11-Pek); and (iii) lower concentrations of the measured elements (deep sediments). The data presented hereby contribute to the monitoring of pollution of the River Danube sediments and give the first view of Ln profile in the studied sediments.
Argumentation und Narration in verschwörungstheoretischen Youtube-Videos
Authors: Niehr Thomas
Published: April 2021

In diesem Beitrag wird das Verhältnis von Argumentation und Narration in sogenannten Verschwörungstheorien näher beleuchtet. Im Anschluss an die in der klassischen Rhetorik beschriebene Funktion dernarratioin einer Gerichtsrede wird der Frage nachgegangen, in welcher Weise narrative Elemente bei verschwörungstheoretischen Argumentationen eingesetzt werden und welche Funktionen sie dabei übernehmen. Am Beispiel ausgewählter Youtube-Videos des Verschwörungstheoretikers Heiko Schrang wird illustriert, wie narrative Elemente eine Argumentation stützen und Rezipient*innen Anschluss an die eigenen Wissensbestände sichern können.
Analyzing development patterns in research networks and technology
Authors: Wolf Patrick , Buchmann Tobias
Published: April 2021

The present paper analyzes development patterns in research networks and technology as well as their co-evolution by the example of the currently highly transformative German automotive industry. We therefore introduce a consistent network-based approach for measuring change in research networks and the technological composition of patents. Our results show that the applied method is particularly useful for identifying structural similarities and main structural changes in research and patent networks. Further, the investigation of the co-evolutionary processes indicates that, regarding the German automotive industry, changes in technology lead to structural changes in the research network.
Infectious Disease Hospital Preparedness: Lessons Learned From the 2019 Measles Outbreak
Authors: Fifolt Matthew , Lee Rachael A , Nafziger Sarah , McCormick Lisa C
Published: April 2021

Objective:

This paper: (1) explores the real and perceived threats to Emergency Departments (EDs) in addressing infectious disease cases in the US, like measles, and (2) identifies priorities for protecting employees, patients, and others stakeholders through hospital preparedness while streamlining processes and managing costs.

Methods:

A case study approach was used to describe the events that triggered an infectious disease emergency response in 1 ED in the southeast. Development of the case study was informed by emergency preparedness literature on Homeland Security Exercise and Evaluation Program processes.

Results:

Hospital staff and administrators identified a number of factors that either positively contributed to disease containment or exacerbated conditions for disease transmission. Successes included early recognition of the potential threat, development of a multidisciplinary taskforce, and implementation of a pre-incident response plan. Challenges comprised of patient flow in crisis response, lab turnaround time, and employee records.

Conclusions:

The threat of exposure challenged daily operations and raised situational awareness among administrators and providers to issues that might arise during an infectious disease exposure. Recording emergency preparedness successes, remediating challenges, and sharing information with others may help minimize the threat of communicable diseases within hospital settings in the future.
Subjective accelerated aging moderates the association between COVID-19 health worries and peritraumatic distress among older adults
Authors: Greenblatt-Kimron Lee , Ring Lia , Hoffman Yaakov , Shrira Amit , Bodner Ehud , Palgi Yuval
Published: April 2021

Background

The present study examined whether subjective accelerated aging moderated the relationship between COVID-19 health worries and COVID-19 peritraumatic distress among older adults.

Method

The sample consisted of 277 older adults (M = 69.58,s.d.= 6.73, range 60–92) who answered an online questionnaire during the outbreak of COVID-19 pandemic in Israel. Participants completed the measures of background characteristics, exposure to COVID-19, COVID-19 health worries, subjective accelerated aging and COVID-19-based peritraumatic distress.

Results

Higher levels of COVID-19 health worries were correlated with higher levels of peritraumatic distress symptoms among older adults. Moreover, those reporting accelerated aging also reported a higher level of peritraumatic distress. Finally, the interaction between COVID-19 health worries and subjective accelerated aging predicted peritraumatic distress, suggesting that COVID-19 worries were associated with peritraumatic distress to a stronger degree among older adults who felt they were aging faster.

Conclusions

These findings indicate that negative views of aging may serve as an amplifying factor for traumatic distress during the COVID-19 pandemic. Although preliminary, the findings provide insight for potential screening and interventions of older adults at risk of developing peritraumatic distress symptoms during the global pandemic.
Optimizing the Measurement of Sexism in Political Surveys
Authors: Schaffner Brian F.
Published: April 2021

Political scientists are paying increasing attention to understanding the role of sexist attitudes on predicting vote choices and opinions on issues. However, the research in this area measures sexist attitudes with a variety of different items and scales. In this paper, I evaluate some of the most prominent contemporary measures of sexism and develop an approach for identifying optimal items based on (1) convergent validity, (2) predictive validity, and (3) distance from politics. I find that a subset of items from the hostile sexism scale exhibit the most desirable measurement properties and I conclude by recommending a simple two- to five-item reduced hostile sexism battery that will allow scholars to efficiently, validly, and consistently measure sexism.
The Ediacaran ‘Miaohe Member’ of South China: new insights from palaeoredox proxies and stable isotope data
Authors: Bridger Paul , Poulton Simon W. , Zhou Ying , Li Chao , Zhang Kun , Shields Graham A.
Published: April 2021

Throughout the Ediacaran Period, variable water-column redox conditions persisted along productive ocean margins due to a complex interplay between nutrient supply and oceanographic restriction. These changing conditions are considered to have influenced early faunal evolution, with marine anoxia potentially inhibiting the development of the ecological niches necessary for aerobic life forms. To understand this link between oxygenation and evolution, the combined geochemical and palaeontological study of marine sediments is preferable. Located in the Yangtze Gorges region of southern China, lagoonal black shales at Miaohe preserve alga and putative metazoans, including Eoandromeda, a candidate total-group ctenophore, thereby providing one example of where integrated study is possible. We present a multi-proxy investigation into water-column redox variability during deposition of these shales (c. 560–551 Ma). For this interval, reactive iron partitioning indicates persistent water-column anoxia, while trace metal enrichments and other geochemical data suggest temporal fluctuations between ferruginous, euxinic and rare suboxic conditions. Although trace metal and total organic carbon values imply extensive basin restriction, sustained trace metal enrichment and δ15Nsed data indicate periodic access to open-ocean inventories across a shallow-marine sill. Lastly, δ13Corg values of between −35‰ and −40‰ allow at least partial correlation of the shales at Miaohe with Member IV of the Doushantuo Formation. This study provides evidence for fluctuating redox conditions in the lagoonal area of the Yangtze platform during late Ediacaran time. If these low-oxygen environments were regionally characteristic, then the restriction of aerobic fauna to isolated environments can be inferred.
Psychiatric comorbidity as predictor and moderator of binge-eating disorder treatment outcomes: an analysis of aggregated randomized controlled trials
Authors: Lydecker Janet A. , Grilo Carlos M.
Published: April 2021

Background

Psychiatric comorbidity is common in binge-eating disorder (BED) but effects on treatment outcomes are unknown. The current study aimed to determine whether psychiatric comorbidity predicted or moderated BED treatment outcomes.

Methods

In total, 636 adults with BED in randomized-controlled trials (RCTs) were assessed prior, throughout, and posttreatment by doctoral research-clinicians using reliably-administered semi-structured interviews, self-report measures, and measured weight. Data were aggregated from RCTs testing cognitive-behavioral therapy, behavioral weight loss, multi-modal (combined pharmacological plus cognitive-behavioral/behavioral), and/or control conditions. Intent-to-treat analyses (all available data) tested comorbidity (mood, anxiety, ‘any disorder’ separately) as predictors and moderators of outcomes. Mixed-effects models tested comorbidity effects on binge-eating frequency, global eating-disorder psychopathology, and weight. Generalized estimating equation models tested binge-eating remission (zero binge-eating episodes during the past month; missing data imputed as failure).

Results

Overall, 41% of patients had current psychiatric comorbidity; 22% had mood and 23% had anxiety disorders. Psychiatric comorbidity did not significantly moderate the outcomes of specific treatments. Psychiatric comorbidity predicted worse eating-disorder psychopathology and higher binge-eating frequency across all treatments and timepoints. Patients with mood comorbidity were significantly less likely to remit than those without mood disorders (30% v. 41%). Psychiatric comorbidity neither predicted nor moderated weight loss.

Conclusions

Psychiatric comorbidity was associated with more severe BED psychopathology throughout treatment but did not moderate outcomes. Findings highlight the need to improve treatments for BED with psychiatric comorbidities but challenge perspectives that combining existing psychological and pharmacological interventions is warranted. Treatment research must identify more effective interventions for BED overall and for patients with comorbidities.
Effectiveness of cognitive remediation in depression: a meta-analysis
Authors: Legemaat Amanda M. , Semkovska Maria , Brouwer Marlies , Geurtsen Gert J. , Burger Huibert , Denys Damiaan , Bockting Claudi L.
Published: April 2021

Background

Preliminary evidence suggests beneficial effects of cognitive remediation in depression. An update of the current evidence is needed. The aim was to systematically assess the effectiveness of cognitive remediation in depression on three outcomes.

Methods

The meta-analysis was pre-registered on PROSPERO (CRD42019124316). PubMed, PsycINFO, Embase and Cochrane Library were searched on 2 February 2019 and 8 November 2020 for peer-reviewed published articles. We included randomized and non-randomized clinical trials comparing cognitive remediation to control conditions in adults with primary depression. Random-effects models were used to calculate Hedges' g, and moderators were assessed using mixed-effects subgroup analyses and meta-regression. Main outcome categories were post-treatment depressive symptomatology (DS), cognitive functioning (CF) and daily functioning (DF).

Results

We identified 5221 records and included 21 studies reporting on 24 comparisons, with 438 depressed patients receiving cognitive remediation and 540 patients in a control condition. We found a small effect on DS (g = 0.28, 95% CI 0.09–0.46, I2 40%), a medium effect on CF (g = 0.60, 95% CI 0.37–0.83, I2 44%) and a small effect on DF (g = 0.22, 95% CI 0.06–0.39, I2 3%). There were no significant effects at follow-up. Confounding bias analyses indicated possible overestimation of the DS and DF effects in the original studies.

Conclusions

Cognitive remediation in depression improves CF in the short term. The effects on DS and DF may have been overestimated. Baseline depressive symptom severity should be considered when administering cognitive remediation.
Prevalence of internalizing disorders, symptoms, and traits across age using advanced nonlinear models
Authors: van Loo Hanna M. , Beijers Lian , Wieling Martijn , de Jong Trynke R. , Schoevers Robert A. , Kendler Kenneth S.
Published: April 2021

Background

Most epidemiological studies show a decrease of internalizing disorders at older ages, but it is unclear how the prevalence exactly changes with age, and whether there are different patterns for internalizing symptoms and traits, and for men and women. This study investigates the impact of age and sex on the point prevalence across different mood and anxiety disorders, internalizing symptoms, and neuroticism.

Methods

We used cross-sectional data on 146 315 subjects, aged 18–80 years, from the Lifelines Cohort Study, a Dutch general population sample. Between 2012 and 2016, five current internalizing disorders – major depression, dysthymia, generalized anxiety disorder, social phobia, and panic disorder – were assessed according to DSM-IV criteria. Depressive symptoms, anxiety symptoms, neuroticism, and negative affect (NA) were also measured. Generalized additive models were used to identify nonlinear patterns across age, and to investigate sex differences.

Results

The point prevalence of internalizing disorders generally increased between the ages of 18 and 30 years, stabilized between 30 and 50, and decreased after age 50. The patterns of internalizing symptoms and traits were different. NA and neuroticism gradually decreased after age 18. Women reported more internalizing disorders than men, but the relative difference remained stable across age (relative risk ~1.7).

Conclusions

The point prevalence of internalizing disorders was typically highest between age 30 and 50, but there were differences between the disorders, which could indicate differences in etiology. The relative gap between the sexes remained similar across age, suggesting that changes in sex hormones around the menopause do not significantly influence women's risk of internalizing disorders.
The contribution of depressive ‘disorder characteristics’ to determinations of prognosis for adults with depression: an individual patient data meta-analysis
Authors: Buckman Joshua E. J. , Saunders Rob , Cohen Zachary D. , Barnett Phoebe , Clarke Katherine , Ambler Gareth , DeRubeis Robert J. , Gilbody Simon , Hollon Steven D. , Kendrick Tony , Watkins Edward , Wiles Nicola , Kessler David , Richards David , Sharp Deborah , Brabyn Sally , Littlewood Elizabeth , Salisbury Chris , White Ian R. , Lewis Glyn , Pilling Stephen
Published: April 2021

Background

This study aimed to investigate general factors associated with prognosis regardless of the type of treatment received, for adults with depression in primary care.

Methods

We searched Medline, Embase, PsycINFO and Cochrane Central (inception to 12/01/2020) for RCTs that included the most commonly used comprehensive measure of depressive and anxiety disorder symptoms and diagnoses, in primary care depression RCTs (the Revised Clinical Interview Schedule: CIS-R). Two-stage random-effects meta-analyses were conducted.

Results

Twelve (n = 6024) of thirteen eligible studies (n = 6175) provided individual patient data. There was a 31% (95%CI: 25 to 37) difference in depressive symptoms at 3–4 months per standard deviation increase in baseline depressive symptoms. Four additional factors: the duration of anxiety; duration of depression; comorbid panic disorder; and a history of antidepressant treatment were also independently associated with poorer prognosis. There was evidence that the difference in prognosis when these factors were combined could be of clinical importance. Adding these variables improved the amount of variance explained in 3–4 month depressive symptoms from 16% using depressive symptom severity alone to 27%. Risk of bias (assessed with QUIPS) was low in all studies and quality (assessed with GRADE) was high. Sensitivity analyses did not alter our conclusions.

Conclusions

When adults seek treatment for depression clinicians should routinely assess for the duration of anxiety, duration of depression, comorbid panic disorder, and a history of antidepressant treatment alongside depressive symptom severity. This could provide clinicians and patients with useful and desired information to elucidate prognosis and aid the clinical management of depression.
Review of infective dose, routes of transmission and outcome of COVID-19 caused by the SARS-COV-2: comparison with other respiratory viruses
Authors: Karimzadeh Sedighe , Bhopal Raj , Nguyen Tien Huy
Published: April 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is pandemic. Prevention and control strategies require an improved understanding of SARS-CoV-2 dynamics. We did a rapid review of the literature on SARS-CoV-2 viral dynamics with a focus on infective dose. We sought comparisons of SARS-CoV-2 with other respiratory viruses including SARS-CoV-1 and Middle East respiratory syndrome coronavirus. We examined laboratory animal and human studies. The literature on infective dose, transmission and routes of exposure was limited specially in humans, and varying endpoints were used for measurement of infection. Despite variability in animal studies, there was some evidence that increased dose at exposure correlated with higher viral load clinically, and severe symptoms. Higher viral load measures did not reflect coronavirus disease 2019 severity. Aerosol transmission seemed to raise the risk of more severe respiratory complications in animals. An accurate quantitative estimate of the infective dose of SARS-CoV-2 in humans is not currently feasible and needs further research. Our review suggests that it is small, perhaps about 100 particles. Further work is also required on the relationship between routes of transmission, infective dose, co-infection and outcomes.
Adjuvant chemotherapy versus observation following neoadjuvant therapy and surgery for resectable stages I–II pancreatic cancer
Authors: Ma Sung Jun , Serra Lucas M. , Bartl Austin J. , Han Hye Ri , Fekrmandi Fatemeh , Iovoli Austin J. , Hermann Gregory M. , Yu Han , Singh Anurag K.
Published: April 2021

Aim:

This National Cancer Database (NCDB) analysis was performed to evaluate the outcomes of adjuvant chemotherapy (AC) versus observation for resected pancreatic adenocarcinoma treated with neoadjuvant therapy (NT).

Materials and methods:

The NCDB was queried for primary stages I–II cT1-3N0-1M0 resected pancreatic adenocarcinoma treated with NT (2004–2015). Baseline patient, tumour and treatment characteristics were extracted. The primary end point was overall survival (OS). With a 6-month conditional landmark, Kaplan–Meier analysis, multivariable Cox proportional hazards method and 1:1 propensity score matching was used to analyse the data.

Results:

A total of 1,737 eligible patients were identified, of which 1,247 underwent post-operative observation compared to 490 with AC. The overall median follow-up was 34·7 months. The addition of AC showed improved survival on the multivariate analysis (HR 0·78, p < 0·001). AC remained statistically significant for improved OS, with a median OS of 26·3 months versus 22·3 months and 2-year OS of 63·9% versus 52·9% for the observation cohort (p < 0·001). Treatment interaction analysis showed OS benefit of AC for patients with smaller tumours.

Findings:

Our findings suggest a survival benefit for AC compared to observation following NT and surgery for resectable pancreatic adenocarcinoma, especially in patients with smaller tumours.
Oxygen False Positives on Habitable Zone Planets Around Sun‐Like Stars
Authors: Krissansen‐Totton Joshua , Fortney Jonathan J. , Nimmo Francis , Wogan Nicholas
Published: April 2021

Oxygen is a promising exoplanet biosignature due to the evolutionary advantage conferred by harnessing starlight for photosynthesis, and the apparent low likelihood of maintaining oxygen‐rich atmospheres without life. Hypothetical scenarios have been proposed for non‐biological oxygen accumulation on planets around late M‐dwarfs, where the extended pre‐main sequence may favor abiotic O2 accumulation. In contrast, abiotic oxygen accumulation on planets around F, G, and K‐type stars is seemingly less likely, provided they possess substantial non‐condensable gas inventories. The comparative robustness of oxygen biosignatures around larger stars has motivated plans for next‐generation telescopes capable of oxygen detection on planets around sun‐like stars. However, the general tendency of terrestrial planets to develop oxygen‐rich atmospheres across a broad range of initial conditions and evolutionary scenarios has not been explored. Here, we use a coupled thermal‐geochemical‐climate model of terrestrial planet evolution to illustrate three scenarios whereby significant abiotic oxygen can accumulate around sun‐like stars, even when significant noncondensable gas inventories are present. For Earth‐mass planets, we find abiotic oxygen can accumulate to modern levels if (1) the CO2:H2O ratio of the initial volatile inventory is high, (2) the initial water inventory exceeds ∼50 Earth oceans, or (3) the initial water inventory is very low (<0.3 Earth oceans). Fortunately, these three abiotic oxygen scenarios could be distinguished from biological oxygen with observations of other atmospheric constituents or characterizing the planetary surface. This highlights the need for broadly capable next‐generation telescopes that are equipped to constrain surface water inventories via time‐resolved photometry and search for temporal biosignatures or disequilibrium combination biosignatures to assess whether oxygen is biogenic.
Influence of Tide‐Induced Unstable Flow on Seawater Intrusion and Submarine Groundwater Discharge
Authors: Fang Yunhai , Zheng Tianyuan , Zheng Xilai , Yang Huiyu , Wang Huan , Walther Marc
Published: April 2021

Recent studies have confirmed the instability of tide‐induced upper saline plume (USP) in tidal beach aquifers. A systematic understanding of how the unstable USP contributes to groundwater flow and salinity distribution is still lacking. Here we used laboratory experiments and numerical simulations to examine the responses of the salinity distribution and submarine groundwater discharge (SGD) to tide‐induced unstable flow. The results revealed that changes in physical forcing conditions (tides and inland freshwater input) drove the transition of the USP from stable to unstable states. Meanwhile, the phase‐averaged SGD and its components fluctuated over time, and their oscillation amplitudes depended on the physical forcing conditions. There was a correlation between USP instability and the fluctuation of water exchange across the aquifer‐sea interface. The fluxes across the aquifer‐sea interface under unstable conditions usually varied considerably over time with a lower frequency in comparison to stable conditions. The extent of seawater intrusion (SWI) measured by the total salt mass stored in the aquifer also varied over time, especially under unstable conditions. The vibration tendency of the total salt mass was opposite to that of the sum of inland freshwater discharge and tide‐induced circulation efflux. For coastal aquifers affected by tides, SWI was dominated by the sum of inland freshwater discharge and tide‐induced circulation efflux, followed by the sum of inland freshwater input and tide‐induced circulation influx. These findings lay the foundation for gaining a better understanding of tide‐induced unstable flow and its potential implications.
The roles of the inhibitory autophagy regulator Rubicon in the heart: A new therapeutic target to prevent cardiac cell death
Authors: Nah Jihoon , Zablocki Daniela , Sadoshima Junichi
Published: April 2021

Autophagy contributes to the maintenance of cardiac homeostasis. The level of autophagy is dynamically altered in heart disease. Although autophagy is a promising therapeutic target, only a few selective autophagy activator candidates have been reported thus far. Rubicon is one of the few endogenous negative regulators of autophagy and a potential target for autophagy-inducing therapeutics. Rubicon was initially identified as a component of the Class III PI3K complex, and it has multiple functions, not only in canonical autophagy but also in endosomal trafficking and inflammatory responses. This review summarizes the molecular action of Rubicon in canonical and noncanonical autophagy. We discuss the roles of Rubicon in cardiac stress and the therapeutic potential of Rubicon in cardiac diseases through its modulation of autophagy.
Correction to: Spatial patterns in phage-Rhizobium coevolutionary interactions across regions of common bean domestication
Authors: Van Cauwenberghe Jannick , Santamaría Rosa I , Bustos Patricia , Juárez Soledad , Ducci Maria Antonella , Fleming Trinidad Figueroa , Etcheverry Angela Virginia , González Víctor
Published: April 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41396-021-00963-5
Anticipated help-seeking for cancer symptoms before and after the coronavirus pandemic: results from the Onco-barometer population survey in Spain
Authors: Petrova Dafina , Pollán Marina , Rodriguez-Barranco Miguel , Garrido Dunia , Borrás Josep M. , Sánchez Maria-José
Published: April 2021

Background

The patient interval—the time patients wait before consulting their physician after noticing cancer symptoms—contributes to diagnostic delays. We compared anticipated help-seeking times for cancer symptoms and perceived barriers to help-seeking before and after the coronavirus pandemic.

Methods

Two waves (pre-Coronavirus: February 2020, N = 3269; and post-Coronavirus: August 2020, N = 1500) of the Spanish Onco-barometer population survey were compared. The international ABC instrument was administered. Pre–post comparisons were performed using multiple logistic and Poisson regression models.

Results

There was a consistent and significant increase in anticipated times to help-seeking for 12 of 13 cancer symptoms, with the largest increases for breast changes (OR = 1.54, 95% CI 1.22–1–96) and unexplained bleeding (OR = 1.50, 1.26–1.79). Respondents were more likely to report barriers to help-seeking in the post wave, most notably worry about what the doctor may find (OR = 1.58, 1.35–1.84) and worry about wasting the doctor’s time (OR = 1.48, 1.25–1.74). Women and older individuals were the most affected.

Conclusions

Participants reported longer waiting times to help-seeking for cancer symptoms after the pandemic. There is an urgent need for public interventions encouraging people to consult their physicians with symptoms suggestive of cancer and counteracting the main barriers perceived during the pandemic situation.
Correction: ZHX2 drives cell growth and migration via activating MEK/ERK signal and induces Sunitinib resistance by regulating the autophagy in clear cell Renal Cell Carcinoma
Authors: Zhu Liangsong , Ding Rong , Yan Hao , Zhang Jin , Lin Zongming
Published: April 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41419-021-03678-9
Directly targeting c-Myc contributes to the anti-multiple myeloma effect of anlotinib
Authors: Cao Yang , Shan Huizhuang , Liu Meng , Liu Jia , Zhang Zilu , Xu Xiaoguang , Liu Yue , Xu Hanzhang , Lei Hu , Yu Miao , Zhang Xingming , Liu Wanting , Bu Zhilei , Fang Zhixiao , Ji Yanjie , Yan Hua , Gu Weiying , Wu Yingli
Published: April 2021

Despite the significant advances in the treatment of multiple myeloma (MM), this disease is still considered incurable because of relapse and chemotherapy resistance, underscoring the need to seek novel therapies with different mechanisms. Anlotinib, a novel multi-targeted tyrosine kinase inhibitor (TKI), has exhibited encouraging antitumor activity in several preclinical and clinical trials, but its effect on MM has not been studied yet. In this study, we found that anlotinib exhibits encouraging cytotoxicity in MM cells, overcomes the protective effect of the bone marrow microenvironment and suppresses tumor growth in the MM mouse xenograft model. We further examined the underlying molecular mechanism and found that anlotinib provokes cell cycle arrest, induces apoptosis and inhibits multiple signaling pathways. Importantly, we identify c-Myc as a novel direct target of anlotinib. The enhanced ubiquitin proteasomal degradation of c-Myc contributes to the cell apoptosis induced by anlotinib. In addition, anlotinib also displays strong cytotoxicity against bortezomib-resistant MM cells. Our study demonstrates the extraordinary anti-MM effect of anlotinib both in vitro and in vivo, which provides solid evidence and a promising rationale for future clinical application of anlotinib in the treatment of human MM.
Spine impairment in mice high-expressing neuregulin 1 due to LIMK1 activation
Authors: Chen Peng , Jing Hongyang , Xiong Mingtao , Zhang Qian , Lin Dong , Ren Dongyan , Wang Shunqi , Yin Dongmin , Chen Yongjun , Zhou Tian , Li Baoming , Fei Erkang , Pan Bing-Xing
Published: April 2021

The genes encoding for neuregulin1 (NRG1), a growth factor, and its receptor ErbB4 are both risk factors of major depression disorder and schizophrenia (SZ). They have been implicated in neural development and synaptic plasticity. However, exactly how NRG1 variations lead to SZ remains unclear. Indeed, NRG1 levels are increased in postmortem brain tissues of patients with brain disorders. Here, we studied the effects of high-level NRG1 on dendritic spine development and function. We showed that spine density in the prefrontal cortex and hippocampus was reduced in mice (ctoNrg1) that overexpressed NRG1 in neurons. The frequency of miniature excitatory postsynaptic currents (mEPSCs) was reduced in both brain regions of ctoNrg1 mice. High expression of NRG1 activated LIMK1 and increased cofilin phosphorylation in postsynaptic densities. Spine reduction was attenuated by inhibiting LIMK1 or blocking the NRG1–LIMK1 interaction, or by restoring NRG1 protein level. These results indicate that a normal NRG1 protein level is necessary for spine homeostasis and suggest a pathophysiological mechanism of abnormal spines in relevant brain disorders.
The ubiquitin ligase NEDD4-2/NEDD4L regulates both sodium homeostasis and fibrotic signaling to prevent end-stage renal disease
Authors: Manning Jantina A. , Shah Sonia S. , Nikolic Andrej , Henshall Tanya L. , Khew-Goodall Yeesim , Kumar Sharad
Published: April 2021

Kidney disease progression can be affected by Na+ abundance. A key regulator of Na+ homeostasis is the ubiquitin ligase NEDD4-2 and its deficiency leads to increased Na+ transport activity and salt-sensitive progressive kidney damage. However, the mechanisms responsible for high Na+ induced damage remain poorly understood. Here we show that a high Na+ diet compromised kidney function in Nedd4-2-deficient mice, indicative of progression toward end-stage renal disease. Injury was characterized by enhanced tubule dilation and extracellular matrix accumulation, together with sustained activation of both Wnt/β-catenin and TGF-β signaling. Nedd4-2 knockout in cortical collecting duct cells also activated these pathways and led to epithelial–mesenchymal transition. Furthermore, low dietary Na+ rescued kidney disease in Nedd4-2-deficient mice and silenced Wnt/β-catenin and TGF-β signaling. Our study reveals the important role of NEDD4-2-dependent ubiquitination in Na+ homeostasis and protecting against aberrant Wnt/β-catenin/TGF-β signaling in progressive kidney disease.
Honey-collecting in prehistoric West Africa from 3500 years ago
Authors: Dunne Julie , Höhn Alexa , Franke Gabriele , Neumann Katharina , Breunig Peter , Gillard Toby , Walton-Doyle Caitlin , Evershed Richard P.
Published: April 2021

Honey and other bee products were likely a sought-after foodstuff for much of human history, with direct chemical evidence for beeswax identified in prehistoric ceramic vessels from Europe, the Near East and Mediterranean North Africa, from the 7thmillennium BC. Historical and ethnographic literature from across Africa suggests bee products, honey and larvae, had considerable importance both as a food source and in the making of honey-based drinks. Here, to investigate this, we carry out lipid residue analysis of 458 prehistoric pottery vessels from the Nok culture, Nigeria, West Africa, an area where early farmers and foragers co-existed. We report complex lipid distributions, comprisingn-alkanes,n-alkanoic acids and fatty acyl wax esters, which provide direct chemical evidence of bee product exploitation and processing, likely including honey-collecting, in over one third of lipid-yielding Nok ceramic vessels. These findings highlight the probable importance of honey collecting in an early farming context, around 3500 years ago, in West Africa.
Toward integrative approaches to study the causal role of neural oscillations via transcranial electrical stimulation
Authors: Beliaeva Valeriia , Savvateev Iurii , Zerbi Valerio , Polania Rafael
Published: April 2021

Diverse transcranial electrical stimulation (tES) techniques have recently been developed to elucidate the role of neural oscillations, but critically, it remains questionable whether neural entrainment genuinely occurs and is causally related to the resulting behavior. Here, we provide a perspective on an emerging integrative research program across systems, species, theoretical and experimental frameworks to elucidate the potential of tES to induce neural entrainment. We argue that such an integrative agenda is a requirement to establish tES as a tool to test the causal role of neural oscillations and highlight critical issues that should be considered when adopting a translational approach.
Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice
Authors: Caballero Benjamin , Bourdenx Mathieu , Luengo Enrique , Diaz Antonio , Sohn Peter Dongmin , Chen Xu , Wang Chao , Juste Yves R. , Wegmann Susanne , Patel Bindi , Young Zapporah T. , Kuo Szu Yu , Rodriguez-Navarro Jose Antonio , Shao Hao , Lopez Manuela G. , Karch Celeste M. , Goate Alison M. , Gestwicki Jason E. , Hyman Bradley T. , Gan Li , Cuervo Ana Maria
Published: April 2021

Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression.
Accelerated phase Ia/b evaluation of the malaria vaccine candidate PfAMA1 DiCo demonstrates broadening of humoral immune responses
Authors: Remarque Edmond J. , Faber Bart W. , Rodriguez Garcia Roberto , Oostermeijer Herman , Sirima Sodiomon B. , Nebie Ouedraogo Issa , Kara Leila , Launay Odile , Houard Sophie , Leroy Odile , Kocken Clemens H. M.
Published: April 2021

Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a candidate malaria vaccine antigen expressed on merozoites and sporozoites. PfAMA1’s polymorphic nature impacts vaccine-induced protection. To address polymorphism, three Diversity Covering (DiCo) protein sequences were designed and tested in a staggered phase Ia/b trial. A cohort of malaria-naive adults received PfAMA1-DiCo adjuvanted with Alhydrogel® or GLA-SE and a cohort of malaria-exposed adults received placebo or GLA-SE adjuvanted PfAMA1 DiCo at weeks 0, 4 and 26. IgG and GIA levels measured 4 weeks after the third vaccination are similar in malaria-naive volunteers and placebo-immunised malaria-exposed adults, and have a similar breadth. Vaccination of malaria-exposed adults results in significant antibody level increases to the DiCo variants, but not to naturally occurring PfAMA1 variants. Moreover, GIA levels do not increase following vaccination. Future research will need to focus on stronger adjuvants and/or adapted vaccination regimens, to induce potentially protective responses in the target group of the vaccine.
Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS
Authors: Ajjugal Yogeeshwar , Kolimi Narendar , Rathinavelan Thenmalarchelvi
Published: April 2021

CGG tandem repeat expansion in the 5′-untranslated region of the fragile X mental retardation-1 (FMR1) gene leads to unusual nucleic acid conformations, hence causing genetic instabilities. We show that the number of G…G (in CGG repeat) or C…C (in CCG repeat) mismatches (other than A…T, T…A, C…G and G…C canonical base pairs) dictates the secondary structural choice of the sense and antisense strands of the FMR1 gene and their corresponding transcripts in fragile X-associated tremor/ataxia syndrome (FXTAS). The circular dichroism (CD) spectra and electrophoretic mobility shift assay (EMSA) reveal that CGG DNA (sense strand of the FMR1 gene) and its transcript favor a quadruplex structure. CD, EMSA and molecular dynamics (MD) simulations also show that more than four C…C mismatches cannot be accommodated in the RNA duplex consisting of the CCG repeat (antisense transcript); instead, it favors an i-motif conformational intermediate. Such a preference for unusual secondary structures provides a convincing justification for the RNA foci formation due to the sequestration of RNA-binding proteins to the bidirectional transcripts and the repeat-associated non-AUG translation that are observed in FXTAS. The results presented here also suggest that small molecule modulators that can destabilize FMR1 CGG DNA and RNA quadruplex structures could be promising candidates for treating FXTAS.
ENSO feedback drives variations in dieback at a marginal mangrove site
Authors: Hickey S. M. , Radford B. , Callow J. N. , Phinn S. R. , Duarte C. M. , Lovelock C. E.
Published: April 2021

Ocean–atmosphere climatic interactions, such as those resulting from El Niño Southern Oscillation (ENSO) are known to influence sea level, sea surface temperature, air temperature, and rainfall in the western Pacific region, through to the north-west Australian Ningaloo coast. Mangroves are ecologically important refuges for biodiversity and a rich store of blue carbon. Locations such as the study site (Mangrove Bay, a World Heritage Site within Ningaloo Marine Park and Cape Range National Park) are at the aridity range-limit which means trees are small in stature, forests small in area, and are potentially susceptible to climate variability such as ENSO that brings lower sea level and higher temperature. Here we explore the relationship between mangrove dieback, and canopy condition with climatic variables and the Southern Oscillation Index (SOI)—a measure of ENSO intensity, through remote sensing classification of Landsat satellite missions across a 29 year period at a north-west Australian site. We find that the SOI, and seasonal mean minimum temperature are strongly correlated to mangrove green canopy (as indicator of live canopy) area. This understanding of climate variations and mangrove temporal heterogeneity (patterns of abundance and condition) highlights the sensitivity and dynamics of this mangrove forest and recommends further research in other arid and semi-arid tropical regions at mangrove range-limits to ascertain the extent of this relationship.
The absence of the caffeine synthase gene is involved in the naturally decaffeinated status of Coffea humblotiana, a wild species from Comoro archipelago
Authors: Raharimalala Nathalie , Rombauts Stephane , McCarthy Andrew , Garavito Andréa , Orozco-Arias Simon , Bellanger Laurence , Morales-Correa Alexa Yadira , Froger Solène , Michaux Stéphane , Berry Victoria , Metairon Sylviane , Fournier Coralie , Lepelley Maud , Mueller Lukas , Couturon Emmanuel , Hamon Perla , Rakotomalala Jean-Jacques , Descombes Patrick , Guyot Romain , Crouzillat Dominique
Published: April 2021

Caffeine is the most consumed alkaloid stimulant in the world. It is synthesized through the activity of three known N-methyltransferase proteins. Here we are reporting on the 422-Mb chromosome-level assembly of the Coffea humblotiana genome, a wild and endangered, naturally caffeine-free, species from the Comoro archipelago. We predicted 32,874 genes and anchored 88.7% of the sequence onto the 11 chromosomes. Comparative analyses with the African Robusta coffee genome (C. canephora) revealed an extensive genome conservation, despite an estimated 11 million years of divergence and a broad diversity of genome sizes within the Coffea genus. In this genome, the absence of caffeine is likely due to the absence of the caffeine synthase gene which converts theobromine into caffeine through an illegitimate recombination mechanism. These findings pave the way for further characterization of caffeine-free species in the Coffea genus and will guide research towards naturally-decaffeinated coffee drinks for consumers.
Enhancing the landscape of colorectal cancer using targeted deep sequencing
Authors: Lee Chul Seung , Song In Hye , Lee Ahwon , Kang Jun , Lee Yoon Suk , Lee In Kyu , Song Young Soo , Lee Sung Hak
Published: April 2021

Targeted next-generation sequencing (NGS) technology detects specific mutations that can provide treatment opportunities for colorectal cancer (CRC) patients. We included 145 CRC patients who underwent surgery. We analyzed the mutation frequencies of common actionable genes and their association with clinicopathological characteristics and oncologic outcomes using targeted NGS. Approximately 97.9% (142) of patients showed somatic mutations. Frequent mutations were observed in TP53 (70%), APC (60%), and KRAS (49%). TP53 mutations were significantly linked to higher overall stage (p = 0.038) and lower disease-free survival (DFS) (p = 0.039). ATM mutation was significantly associated with higher tumor stage (p = 0.012) and shorter overall survival (OS) (p = 0.041). Stage 3 and 4 patients with ATM mutations (p = 0.023) had shorter OS, and FBXW7 mutation was significantly associated with shorter DFS (p = 0.002). However, the OS of patients with or without TP53, RAS, APC, PIK3CA, and SMAD4 mutations did not differ significantly (p = 0.59, 0.72, 0.059, 0.25, and 0.12, respectively). Similarly, the DFS between patients with RAS, APC, PIK3CA, and SMAD4 mutations and those with wild-type were not statistically different (p = 0.3, 0.79, 0.13, and 0.59, respectively). In multivariate Cox regression analysis, ATM mutation was an independent biomarker for poor prognosis of OS (p = 0.043). A comprehensive analysis of the molecular markers for CRC can provide insights into the mechanisms underlying disease progression and help optimize a personalized therapy.
A meta-analysis indicating extra-short implants (≤ 6 mm) as an alternative to longer implants (≥ 8 mm) with bone augmentation
Authors: Yu Xiaoran , Xu Ruogu , Zhang Zhengchuan , Yang Yang , Deng Feilong
Published: April 2021

Extra-short implants, of which clinical outcomes remain controversial, are becoming a potential option rather than long implants with bone augmentation in atrophic partially or totally edentulous jaws. The aim of this study was to compare the clinical outcomes and complications between extra-short implants (≤ 6 mm) and longer implants (≥ 8 mm), with and without bone augmentation procedures. Electronic (via PubMed, Web of Science, EMBASE, Cochrane Library) and manual searches were performed for articles published prior to November 2020. Only randomized controlled trials (RCTs) comparing extra-short implants and longer implants in the same study reporting survival rate with an observation period at least 1 year were selected. Data extraction and methodological quality (AMSTAR-2) was assessed by 2 authors independently. A quantitative meta-analysis was performed to compare the survival rate, marginal bone loss (MBL), biological and prosthesis complication rate. Risk of bias was assessed with the Cochrane risk of bias tool 2 and the quality of evidence was determined with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. 21 RCTs were included, among which two were prior registered and 14 adhered to the CONSORT statement. No significant difference was found in the survival rate between extra-short and longer implant at 1- and 3-years follow-up (RR: 1.002, CI 0.981 to 1.024,P = 0.856 at 1 year; RR: 0.996, CI 0.968 to 1.025,P  = 0.772 at 3 years, moderate quality), while longer implants had significantly higher survival rate than extra-short implants (RR: 0.970, CI 0.944 to 0.997,P < 0.05) at 5 years. Interestingly, no significant difference was observed when bone augmentations were performed at 5 years (RR: 0.977, CI 0.945 to 1.010,P = 0.171 for reconstructed bone; RR: 0.955, CI 0.912 to 0.999,P < 0.05 for native bone). Both the MBL (from implant placement) (WMD: − 0.22, CI − 0.277 to − 0.164,P < 0.01, low quality) and biological complications rate (RR: 0.321, CI 0.243 to 0.422,P < 0.01, moderate quality) preferred extra-short implants. However, there was no significant difference in terms of MBL (from prosthesis restoration) (WMD: 0.016, CI − 0.036 to 0.068,P = 0.555, moderate quality) or prosthesis complications rate (RR: 1.308, CI 0.893 to 1.915,P = 0.168, moderate quality). The placement of extra-short implants could be an acceptable alternative to longer implants in atrophic posterior arch. Further high-quality RCTs with a long follow-up period are required to corroborate the present outcomes.

Registration numberThe review protocol was registered with PROSPERO (CRD42020155342).