bluuebunny/crossref_metadata_2025 huggingface dataset:
The Peptidyl-prolyl Isomerase Pin1 in Neuronal Signaling: from Neurodevelopment to Neurodegeneration
Authors: Fagiani Francesca , Govoni Stefano , Racchi Marco , Lanni Cristina
Published: October 2020

The peptidyl-prolyl isomerase Pin1 is a unique enzyme catalyzing the isomerization of the peptide bond between phosphorylated serine-proline or threonine-proline motifs in proteins, thereby regulating a wide spectrum of protein functions, including folding, intracellular signaling, transcription, cell cycle progression, and apoptosis. Pin1 has been reported to act as a key molecular switch inducing cell-type-specific effects, critically depending on the different phosphorylation patterns of its targets within different biological contexts. While its implication in proliferating cells, and, in particular, in the field of cancer, has been widely characterized, less is known about Pin1 biological functions in terminally differentiated and post-mitotic neurons. Notably, Pin1 is widely expressed in the central and peripheral nervous system, where it regulates a variety of neuronal processes, including neuronal development, apoptosis, and synaptic activity. However, despite studies reporting the interaction of Pin1 with neuronal substrates or its involvement in specific signaling pathways, a more comprehensive understanding of its biological functions at neuronal level is still lacking. Besides its implication in physiological processes, a growing body of evidence suggests the crucial involvement of Pin1 in aging and age-related and neurodegenerative diseases, including Alzheimer’s disease, Parkinson disease, frontotemporal dementias, Huntington disease, and amyotrophic lateral sclerosis, where it mediates profoundly different effects, ranging from neuroprotective to neurotoxic. Therefore, a more detailed understanding of Pin1 neuronal functions may provide relevant information on the consequences of Pin1 deregulation in age-related and neurodegenerative disorders.
Cytoreductive surgery and HIPEC in colorectal cancer—did we get hold of the wrong end of the stick?
Authors: Yurttas Can , Fisher Oliver M. , Cortés-Guiral Delia , Haen Sebastian P. , Königsrainer Ingmar , Königsrainer Alfred , Beckert Stefan , Liauw Winston , Löffler Markus W.
Published: October 2020

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are a multimodal treatment approach combining surgical interventions of varying extent with administration of heated cytostatic drugs flushed through the abdominal cavity. Hitherto, this treatment has been popular for peritoneal metastasis (PM), e.g. from colorectal cancer (CRC). Recent randomized controlled trials (RCT) question the benefit of HIPEC in its present form for CRC treatment and raise fundamental issues, eliciting discussions and expert statements regarding HIPEC relevance and interpretation of these results. Unfortunately, such discussions have to remain uninformed, due to the lacking publication of crucial peer reviewed RCT results. Novel basic research aware of HIPEC futility suggests there may be systematic limitations. Innovative modelling approaches for HIPEC may shed light on the reasons for therapeutic failure of frequently used drugs and may lead the way to select better alternatives and/or more rational approaches for the design of HIPEC procedures (e.g. regarding exposure time or temperature). Available evidence strongly supports the notion that CRS is the mainstay for the treatment effects observed in PM from CRC. Unfortunately, HIPEC has become a surrogate for surgical expertise in the field and optimal surgery may therefore outweigh the potentially harmful effects of HIPEC treatment, particularly in lieu of modern systemic chemotherapies. The current situation which frequently is assumed to be deadlocked should be regarded as a challenge to investigate HIPEC with well-designed prospective clinical trials, potentially even constituting an opportunity for introducing innovative trial designs that solve the multifaceted issues of a very heterogeneous treatment approach.
Professional Development Track to Prepare Future Academic Clinicians
Authors: Traylor K. Marie , Cervantes Jorge L. , Perry Cynthia N.
Published: October 2020

Professional development is instrumental in the success of professionals and trainees in academic medicine. In response to medical student feedback requesting additional professional development opportunities, the Foster School of Medicine developed a distinction program, the Pathway for Preparing Academic Clinicians (PPAC), designed to deliver sought-after skill development and foundational knowledge in the three primary activities of academic medicine: medical education, research, and patient care. This distinction program addresses a curricular gap as identified by students and common to many UME curricula and also provides an opportunity for residency programs to identify student achievement within a pass/fail program.
The Off-Axis IBII Test for Composites
Authors: Parry S. , Fletcher L. , Pierron F.
Published: October 2020

Composite components regularly experience dynamic loads in service. Despite this, it is still difficult to obtain accurate mechanical properties of composite materials under high strain rate conditions. In this study, a new application of the Image-Based Inertial Impact (IBII) test methodology was developed, to generate an accurate in-plane transverse and shear moduli dataset from unidirectional (UD) off-axis composite specimens. The obtained dataset was consistent across different sample configurations, where results from the UD45$$^{\circ }$$∘off-axis specimens agreed well with the UD90$$^{\circ }$$∘values. Validation of the shear modulus identification was also undertaken by comparing the results from the UD90$$^{\circ }$$∘and UD45$$^{\circ }$$∘specimens with a multi-directional (MD) configuration. Here, it was found that MD±45$$^{\circ }$$∘specimen shear modulus values where marginally lower than that from the UD specimens, in accordance with the lower fibre volume fraction of the MD laminate. Low strain rate sensitivities in the$$0.5-2\times$$0.5-2×10$$^{3}$$3 $$\hbox {s}^{-1}$$s-1regime evidenced in this work suggest previously published data (often from split-Hopkinson bar tests) may include both a material and systemi.e.testing apparatus response.
Beating the bias in facial recognition technology
Authors: Lunter Jan
Published: October 2020

In 2019, San Francisco became the first US city to ban facial recognition technology (FRT), specifically vetoing its use by police and other agencies 1 . Since then, several other American cities have implemented their own similar FRT bans, with Boston's city councillors 2 explicitly highlighting one particular issue: the technology's bias.
Facing up to the new world of border control
Authors: Steffens Frank
Published: October 2020

Every decade brings its challenges, and while it's true that the 2020 global Covid-19 pandemic has presented one of the biggest that many of us have faced, we need to prepare for what the post-Covid world will look like. Global travel may have ground to a halt during this year, but as planes take to the skies again and as more land, sea and air borders are re-opened, governments and border control authorities are once again focused on ensuring their borders remain safe and their newly implemented measures are future-proof.
Editorial
Authors: Mansfield-Devine Steve
Published: October 2020

The farce surrounding TikTok and the various attempts to ban and buy it serves to remind us that there is always an element of theatre when it comes to security. The popularity of the platform has been officially classified as a national security risk (in the US, anyway), but the truth has more to do with political grandstanding.
PKI is key to securing a post-Covid remote workforce
Authors: Trzupek Brian
Published: October 2020

In just a few short months, the Covid-19 outbreak has dramatically changed the way that global employees work. In a recent IDC survey, respondents said they expect nearly 30% of their workforce will be working from home in 2021, compared to approximately 6% of their workforce prior to the pandemic. 1

With the Covid-19 outbreak, analysts estimate that we have witnessed two years of IT digital transformation in two months, and many of the changes are here to stay.

Most organisations were forced to shift employees to remote work in just weeks or even days. The switchover has opened the door to a flood of new security threats. Multifactor authentication, such as PKI certificates and passwords, is the best approach to apply flexible, scalable security to protect networks and their users in today's world, explains Brian Trzupek of DigiCert.
Inpatient antibiotic utilization in the Veterans’ Health Administration during the coronavirus disease 2019 (COVID-19) pandemic
Authors: Dieringer Thomas D. , Furukawa Daisuke , Graber Christopher J. , Stevens Vanessa W. , Jones Makoto M. , Rubin Michael A. , Goetz Matthew Bidwell
Published: October 2020

Antibiotic prescribing practices across the Veterans’ Health Administration (VA) experienced significant shifts during the coronavirus disease 2019 (COVID-19) pandemic. From 2015 to 2019, antibiotic use between January and May decreased from 638 to 602 days of therapy (DOT) per 1,000 days present (DP), while the corresponding months in 2020 saw antibiotic utilization rise to 628 DOT per 1,000 DP.
Effects of dietary curcumin on growth, antioxidant capacity, fatty acid composition and expression of lipid metabolism-related genes of large yellow croaker fed a high-fat diet
Authors: Ji Renlei , Xiang Xiaojun , Li Xueshan , Mai Kangsen , Ai Qinghui
Published: October 2020

A 10-week feeding trial was conducted to investigate the effect of dietary curcumin (CC) on growth antioxidant responses, fatty acid composition, and expression of lipid metabolism-related genes of large yellow croaker fed a high-fat diet (HFD). Four diets (lipid level at 18 %) were formulated with different levels of curcumin (0, 0·02, 0·04 and 0·06 %). The best growth performance was found in the 0·04 % curcumin group, with the body and hepatic lipid levels lower than the control group (0 % CC). The content of TAG, total cholesterol and LDL-cholesterol was the least in the 0·06 % curcumin group. The lowest malondialdehyde and the highest superoxide dismutase, catalase and total antioxidant capacity were observed in the 0·04 % curcumin group. The 0·04 % curcumin group had higher expression of Δ6fad, elovl5 and elovl4 and showed higher hepatic n-6 and n-3 PUFA. Expression of ppara, cpt1, and aco was significantly increased, while expression of srebp1 and fas was dramatically decreased in curcumin groups compared with the control group. Overall, 0·04 % curcumin supplementation could mitigate the negative effects caused by HFD and promote growth via reducing hepatic lipid deposition, improving antioxidant activity and increasing PUFA of large yellow croaker. To conclude, abnormal hepatic lipid deposition was probably due to increased fatty acid oxidation and reduced de novo synthesis of fatty acids.
Quantitative author inputs to Earth science research publications: survey results, insights and potential applications
Authors: Ali Jason R.
Published: October 2020

Results are reported of what is believed to be the first survey of the quantitative contributions Earth scientists make to their research publications. Based on a return of 26 (from 45; 254 total documents), two key patterns are observed. For most articles, there is a steady decrease in the roles of the first through fifth authors. The former fall from 65 ± 14% for two-author outputs, to 52 ± 9% for five, to 46 ± 10% for ten; fifth authors are perceived as having contributed 5–6%. The term ‘balanced’ is used to describe such contributor lists. The second pattern, which is labelled ‘imbalanced’, is recognized with teams of five or more and involves the first author shouldering a disproportionately large amount of the work; consequently, the inputs of the third and lesser authors range from small to negligible (5–1%). In some cases, it is observed in a few of a researcher’s publications (≤3); in others, it is more pervasive. There are two basic explanations: estimation problems and excessive numbers of authors, which can be split into two and three subcategories, respectively. The key features of the survey data are dwelt upon. The work concludes with an exploration of a proposed H-Index-type metric that is weighted by the contribution fractions a researcher makes to their publications. This, I contend, would be more reflective of their impact.
Multilevel influences of women’s empowerment and economic resources on risky sexual behaviour among young women in Zomba district, Malawi
Authors: Ward-Peterson Melissa , Fennie Kristopher , Baird Sarah , Coxe Stefany , Trepka Mary Jo , Madhivanan Purnima
Published: October 2020

Gender disparities are pronounced in Zomba district, Malawi. Among women aged 15–49 years, HIV prevalence is 16.8%, compared with 9.3% among men of the same age. Complex structural factors are associated with risky sexual behaviour leading to HIV infection. This study’s objective was to explore associations between multilevel measures of economic resources and women’s empowerment with risky sexual behaviour among young women in Zomba. Four measures of risky sexual behaviour were examined: ever had sex, condom use and two indices measuring age during sexual activity and partner history. Multilevel regression models and regression models with cluster-robust standard errors were used to estimate associations, stratified by school enrolment status. Among the schoolgirl stratum, the percentage of girls enrolled in school at the community level had protective associations with ever having sex (OR = 0.76; 95% CI: 0.60, 0.96) and condom use (OR = 1.06; 95% CI: 1.01, 1.11). Belief in the right to refuse sex was protective against ever having sex (OR = 0.76; 95% CI: 0.60, 0.96). Participants from households with no secondary school education had higher odds of ever having sex (OR = 1.59; 95% CI: 1.14, 2.22). Among the dropout stratum, participants who had not achieved a secondary school level of education had riskier Age Factor and Partner History Factor scores (β = 0.51; 95% CI: 0.23, 0.79, and β = 0.24; 95% CI: 0.07, 0.41, respectively). Participants from households without a secondary school level of education had riskier Age Factor scores (β = 0.26; 95% CI: 0.03, 0.48). Across strata, the most consistent variables associated with risky sexual behaviour were those related to education, including girl’s level of education, highest level of education of her household of origin and the community percentage of girls enrolled in school. These results suggest that programmes seeking to reduce risky sexual behaviour among young women in Malawi should consider the role of improving access to education at multiple levels.
Parent perspectives on preschoolers’ movement and dietary behaviours: a qualitative study in Soweto, South Africa
Authors: Klingberg Sonja , van Sluijs Esther MF , Draper Catherine E
Published: October 2020

Objective:

Childhood obesity is of increasing concern in South Africa, and interventions to promote healthy behaviours related to obesity in children are needed. Young children in urban low-income settings are particularly at risk of excess adiposity. The current study aimed to describe how parents of preschool children in an urban South African township view children’s movement and dietary behaviours, and associated barriers and facilitators.

Design:

A contextualist qualitative design was utilised with in-depth interviews conducted in the home setting and analysed using reflexive thematic analysis. Field notes were used to contextualise findings.

Setting:

Four neighbourhoods in a predominantly low-income urban township.

Participants:

Sixteen parents (fourteen mothers, two fathers) of preschool-age children were recruited via preschools.

Results:

Four themes were developed: children’s autonomy and the limits of parental control; balancing trust and fears; the appeal of screens; and aspirations and pressures of parenthood. Barriers to healthy behaviours included children’s food preferences, aspirations and pressures to consume unhealthy foods, other adults giving children snacks, lack of safe places to play, unhealthy food environments and underlying structural factors. Facilitators included set routines, the preschool environment, safe places to play and availability of healthy foods.

Conclusions:

Low-income families in Soweto face many structural challenges that cannot easily be addressed through public health interventions, but there may be opportunities for behavioural interventions targeting interpersonal and organisational aspects, such as bedtime routines and preschool snacks, to achieve positive changes. More research on preschoolers’ movement and dietary behaviours, and related interventions, is needed in South Africa.
Justifying supranational responses to the anti-constitutionalist challenge: Applying liberal multiculturalism as a background theory
Authors: KÖRTVÉLYESI ZSOLT , MAJTÉNYI BALÁZS
Published: October 2020

The European Union is bound to respect the national identities of member states. States might, on occasion, define their national identities in ways that breach inclusive constitutional values (e.g. equality) protected under TEU Article 2. The assumption behind the recognition of diverse constitutional identities is the peaceful coexistence of both, which is challenged by illiberal national developments. We see the relationship between the constitutional recognition of exclusive values (e.g. dominant ethnicity or religion) and inclusive constitutional values as a zero-sum game; every gain by the proponents of emergent authoritarianism translates to a loss for constitutional democracy. While exclusive norms appear in virtually every constitutional system, a critical mass of exclusive values can lead to the hollowing out of a democratic order, both at the national and supranational levels. To try to identify the line where this shift happens, we rely on the limits of toleration and recognition of exclusive norms and identity elements of minority communities in liberal theories of multiculturalism (e.g. Raz, Taylor, Kymlicka). We think that the case of illiberal minorities raises structurally similar theoretical questions, insights and experiences as the dilemma defined above, namely the challenge of illiberal states undermining fundamental EU values.
African Humid Period Precipitation Sustained by Robust Vegetation, Soil, and Lake Feedbacks
Authors: Chandan Deepak , Peltier W. Richard
Published: October 2020

The African Humid Period (∼11,000–5,000 years before present) was the most recent of several precessionally paced wet intervals during which an increase in the Northern Hemisphere summer incoming solar radiation intensifies the West African Monsoon leading to dramatic changes over northern Africa. However, insolation anomaly alone is not sufficient and feedbacks are essential for further amplification of the monsoon. The most significant feedbacks derive from the land surface, arising from changes to vegetation, soil properties, and distribution of surface water. We show that in contrast to previous studies that have explored the individual impacts of these feedbacks, a modern climate model yields a much greater increase in precipitation in response to their collective effect. Agreement with proxies is improved while the desert‐steppe transition is pushed further northward than in any previous study. In the West African Sahel, intensities of summer daily mean and extreme precipitation increase by 150% and 90%, respectively.
Ice Water Content as a Precursor to Tropical Cyclone Rapid Intensification
Authors: Wu S.‐N. , Soden B. J. , Alaka G. J.
Published: October 2020

This study examines how the structure and amount of cloud ice water content are related to rates of tropical cyclone (TC) intensification using CloudSat profiling radar measurements and simulations from the Hurricane Weather Research and Forecasting (HWRF) model. Observational studies have demonstrated the signal of TC intensification in the passive satellite measurements of frozen water concentration. However, the vertical and horizontal resolution of passive satellite observations are limited. CloudSat measurements and HWRF simulations provide high‐resolution data sets of ice water content to better understand its relationship with the rate of TC intensification. It is found that rapidly intensifying TCs have larger ice water content compared to TCs with slower intensification rates. Similar results are obtained even after accounting for the effect of initial TC intensity. Such precursors of rapidly intensifying TCs may be used to better understand and improve the prediction of TC intensification.
Measuring Global Mean Sea Level Changes With Surface Drifting Buoys
Authors: Elipot Shane
Published: October 2020

Combining ocean model data and in situ Lagrangian data, I show that an array of surface drifting buoys tracked by a Global Navigation Satellite System (GNSS), such as the Global Drifter Program, could provide estimates of global mean sea level (GMSL) and its changes, including linear decadal trends. For a sustained array of 1,250 globally distributed buoys with a standardized design, I demonstrate that GMSL decadal linear trend estimates with an uncertainty less than 0.3 mm yr−1 could be achieved with GNSS daily random error of 1.6 m or less in the vertical direction. This demonstration assumes that controlled vertical position measurements could be acquired from drifting buoys, which is yet to be demonstrated. Development and implementation of such measurements could ultimately provide an independent and resilient observational system to infer natural and anthropogenic sea level changes, augmenting the ongoing tide gauge and satellites records.
The Role of Water Flow and Dispersive Fluxes in the Dissolution of CO2 in Deep Saline Aquifers
Authors: Michel‐Meyer Itamar , Shavit Uri , Tsinober Avihai , Rosenzweig Ravid
Published: October 2020

One of the important mechanisms in CO2 storage is dissolution trapping. The dissolution of CO2 in aquifer brines increases the brine density and leads to hydrodynamic instabilities, formation of CO2‐rich fingers, and a desirable acceleration of the CO2 dissolution. In recent decades, there has been an intensive effort to identify suitable deep aquifers for CO2 sequestration. Despite reports that background horizontal flow exists in many of these aquifers, few numerical studies have addressed whether background flow affects the dissolution process. These studies had no available measurements to support their results. Here, we report on laboratory experiments, using a dyed mixture of methanol and ethylene‐glycol (MEG) as a CO2 analog. The effect of an imposed horizontal water flow was investigated by injecting MEG from above into a cell filled with glass beads. An imaging system was used to provide concentration maps, which were analyzed to calculate dissolution rates and to evaluate the characteristics of the convective fingers. The results show that background flow leads to suppression of the fingers' formation, a fivefold decrease of the fingers' wave number, and a twofold decrease in their propagation rate. Therefore, it was expected that the dissolution rate would also be suppressed, consistent with previous numerical results. However, our results show that the dissolution rate was hardly affected by the background flow. We postulate that the horizontal flow results in a trade‐off between the suppression of the convective flux and the enhancement of dispersive fluxes, resulting in negligible net influence on the dissolution rate.
Colon and liver tissue damage detection using methylated SESN3 and PTK2B genes in circulating cell-free DNA in patients with acute graft-versus-host disease
Authors: Waterhouse Miguel , Pennisi Sandra , Pfeifer Dietmar , Deuter Max , von Bubnoff Nikolas , Scherer Florian , Strüssmann Tim , Wehr Claudia , Duyster Justus , Bertz Hartmut , Finke Jürgen , Duque-Afonso Jesus
Published: October 2020

Cell-free DNA (cfDNA) has been investigated in acute graft-versus-host disease (aGvHD) following allogeneic cell transplantation (HSCT). Identifying the tissue of origin of cfDNA in patients with aGvHD is relevant particularly when a biopsy is not feasible. We investigate the cfDNA tissue of origin in patients with aGvHD using methylated gene biomarkers. Patients with liver, colon, or skin aGvHD (n = 28) were analyzed. Liver- and colon-derived cfDNA was measured using a colon- (SESN3) and liver (PTK2B)-specific methylation marker with digital droplet PCR. A statistically significant difference (p < 0.001) in PTK2B and SESN3 concentration was observed between patients with colon or liver GvHD and the control group. For SESN3 and PTK2B the area under the curve in the receiver-operating characteristic (ROC) space was 0.952 (95% CI, 0.888–1 p < 0.001) and 0.971 (95% CI, 0.964–1 p < 0.001), respectively. Thresholds to differentiate aGvHD from non-aGvHD in colon were 0 (sensitivity: 0.905; specificity: 0.989) and liver 1.5 (sensitivity: 0.928; specificity: 0.910). Clinical improvement of liver or colon aGvHD resulted in PTK2B and SESN3 reduced concentration. Whereas, in those patients without improvement the PTK2B and SESN3 level remained stable or increased. The PTK2B liver-specific marker and the SESN3 colon-specific marker and their longitudinal analysis might improve aGvHD detection.
Upregulation of KCNQ1OT1 promotes resistance to stereotactic body radiotherapy in lung adenocarcinoma by inducing ATG5/ATG12-mediated autophagy via miR-372-3p
Authors: He Huanyu , Song Xinmao , Yang Zuozhang , Mao Yuchi , Zhang Kunming , Wang Yuanyuan , Su Bin , Li Qiutian , Chen Hong , Li Yi
Published: October 2020

Stereotactic body radiotherapy (SBRT) has emerged as a standard treatment for non-small-cell lung cancer. However, its therapeutic advantages are limited with the development of SBRT resistance. The SBRT-resistant cell lines (A549/IR and H1975/IR) were established after exposure with hypofractionated irradiation. The differential lncRNAs were screened by microarray assay, then the expression was detected in LUAD tumor tissues and cell lines by qPCR. The influence on radiation response was assessed via in vitro and in vivo assays, and autophagy levels were evaluated by western blot and transmission electron microscopy. Bioinformatics prediction and rescue experiments were used to identify the pathways underlying SBRT resistance. High expression of KCNQ1OT1 was identified in LUAD SBRT-resistant cells and tissues, positively associated with a large tumor, advanced clinical stage, and a lower response rate to concurrent therapy. KCNQ1OT1 depletion significantly resensitized A549/IR and H1975/IR cells to radiation by inhibiting autophagy, which could be attenuated by miR-372-3p knockdown. Furthermore, autophagy-related 5 (ATG5) and autophagy-related 12 (ATG12) were confirmed as direct targets of miR-372-3p. Restoration of either ATG5 or ATG12 abrogated miR-372-3p-mediated autophagy inhibition and radiosensitivity. Our data describe that KCNQ1OT1 is responsible for SBRT resistance in LUAD through induction of ATG5- and ATG12-dependent autophagy via sponging miR-372-3p, which would be a potential strategy to enhance the antitumor effects of radiotherapy in LUAD.
Importin 13 promotes NSCLC progression by mediating RFPL3 nuclear translocation and hTERT expression upregulation
Authors: Zohud Bisan Abdalfatah , Guo Ping , Zohud Batoul Abdalfatah , Li Fengzhou , Hao Jiao J. , Shan Xiu , Yu Wendan , Guo Wei , Qin Yu , Cai Xin
Published: October 2020

Our previous studies have reported that RFPL3 protein exerts its unique function as a transcriptional factor of hTERT promoter after being transported into the lung cancer cell nucleus. However, the detailed mechanism by which RFPL3 undergoes nuclear transport has not been reported yet. Here, we identified RFPL3 as a potential import cargo for IPO13, which was found to be overexpressed in NSCLC cells and tissues. IPO13 interacted with RFPL3 in lung cancer cells, and the knockdown of IPO13 led to the cytoplasmic accumulation of RFPL3, the decreased anchoring of RFPL3 at hTERT promoter, and the downregulation of hTERT expression. Moreover, IPO13 silencing suppressed tumor growth in vitro and in vivo. IHC analysis confirmed the positive correlation between the expression levels of IPO13 and hTERT in the tumor tissues from patients with lung cancer. Furthermore, the mechanistic study revealed that IPO13 recognized RFPL3 via a functional nuclear localization signal (NLS), which is located in the B30.2 domain at the C-terminal region of RFPL3. Of note, the presence of EGFR mutations was significantly related to the increased IPO13 expression. The EGFR-TKI Osimertinib downregulated IPO13 expression level in NSCLC cell lines with EGFR mutations, but not in EGFR wild-type ones. In summary, our data suggest that inhibition of IPO13 transport activity itself might be an alternative and potential therapeutic strategy for NSCLC.
Wipi3 is essential for alternative autophagy and its loss causes neurodegeneration
Authors: Yamaguchi Hirofumi , Honda Shinya , Torii Satoru , Shimizu Kimiko , Katoh Kaoru , Miyake Koichi , Miyake Noriko , Fujikake Nobuhiro , Sakurai Hajime Tajima , Arakawa Satoko , Shimizu Shigeomi
Published: October 2020

Alternative autophagy is an Atg5/Atg7-independent type of autophagy that contributes to various physiological events. We here identify Wipi3 as a molecule essential for alternative autophagy, but which plays minor roles in canonical autophagy. Wipi3 binds to Golgi membranes and is required for the generation of isolation membranes. We establish neuron-specific Wipi3-deficient mice, which show behavioral defects, mainly as a result of cerebellar neuronal loss. The accumulation of iron and ceruloplasmin is also found in the neuronal cells. These abnormalities are suppressed by the expression of Dram1, which is another crucial molecule for alternative autophagy. Although Atg7-deficient mice show similar phenotypes to Wipi3-deficient mice, electron microscopic analysis shows that they have completely different subcellular morphologies, including the morphology of organelles. Furthermore, most Atg7/Wipi3 double-deficient mice are embryonic lethal, indicating that Wipi3 functions to maintain neuronal cells via mechanisms different from those of canonical autophagy.
WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion
Authors: Rodriguez-Hernandez Irene , Maiques Oscar , Kohlhammer Leonie , Cantelli Gaia , Perdrix-Rosell Anna , Monger Joanne , Fanshawe Bruce , Bridgeman Victoria L. , Karagiannis Sophia N. , Penin Rosa M. , Marcolval Joaquim , Marti Rosa M. , Matias-Guiu Xavier , Fruhwirth Gilbert O. , Orgaz Jose L. , Malanchi Ilaria , Sanz-Moreno Victoria
Published: October 2020

Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. Notably, melanoma can disseminate using amoeboid invasive strategies. We show here that high Myosin II activity, high levels of ki-67 and high tumour-initiating abilities are characteristic of invasive amoeboid melanoma cells. Mechanistically, we find that WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II and plays a crucial role in regulating tumour-initiating potential, local invasion and distant metastasis formation. Importantly, amoeboid melanoma cells express both proliferative and invasive gene signatures. As such, invasive fronts of human and mouse melanomas are enriched in amoeboid cells that are also ki-67 positive. This pattern is further enhanced in metastatic lesions. We propose eradication of amoeboid melanoma cells after surgical removal as a therapeutic strategy.
Electrification at water–hydrophobe interfaces
Authors: Nauruzbayeva Jamilya , Sun Zhonghao , Gallo Adair , Ibrahim Mahmoud , Santamarina J. Carlos , Mishra Himanshu
Published: October 2020

The mechanisms leading to the electrification of water when it comes in contact with hydrophobic surfaces remains a research frontier in chemical science. A clear understanding of these mechanisms could, for instance, aid the rational design of triboelectric generators and micro- and nano-fluidic devices. Here, we investigate the origins of the excess positive charges incurred on water droplets that are dispensed from capillaries made of polypropylene, perfluorodecyltrichlorosilane-coated glass, and polytetrafluoroethylene. Results demonstrate that the magnitude and sign of electrical charges vary depending on: the hydrophobicity/hydrophilicity of the capillary; the presence/absence of a water reservoir inside the capillary; the chemical and physical properties of aqueous solutions such as pH, ionic strength, dielectric constant and dissolved CO2 content; and environmental conditions such as relative humidity. Based on these results, we deduce that common hydrophobic materials possess surface-bound negative charge. Thus, when these surfaces are submerged in water, hydrated cations form an electrical double layer. Furthermore, we demonstrate that the primary role of hydrophobicity is to facilitate water-substrate separation without leaving a significant amount of liquid behind. These results advance the fundamental understanding of water-hydrophobe interfaces and should translate into superior materials and technologies for energy transduction, electrowetting, and separation processes, among others.
A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics
Authors: Lyngbakken Magnus Nakrem , Berdal Jan-Erik , Eskesen Arne , Kvale Dag , Olsen Inge Christoffer , Rueegg Corina Silvia , Rangberg Anbjørg , Jonassen Christine Monceyron , Omland Torbjørn , Røsjø Helge , Dalgard Olav
Published: October 2020

Here, we randomized 53 patients hospitalized with coronavirus disease 2019 (COVID-19) to hydroxychloroquine therapy (at a dose of 400 mg twice daily for seven days) in addition to standard care or standard care alone (ClinicalTrials.gov Identifier, NCT04316377). All severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients 18 years of age or older were eligible for study inclusion if they had moderately severe COVID-19 at admission. Treatment with hydroxychloroquine did not result in a significantly greater rate of decline in SARS-CoV-2 oropharyngeal viral load compared to standard care alone during the first five days. Our results suggest no important antiviral effect of hydroxychloroquine in humans infected with SARS-CoV-2.
Mechanisms of telomerase inhibition by oxidized and therapeutic dNTPs
Authors: Sanford Samantha L. , Welfer Griffin A. , Freudenthal Bret D. , Opresko Patricia L.
Published: October 2020

Telomerase is a specialized reverse transcriptase that adds GGTTAG repeats to chromosome ends and is upregulated in most human cancers to enable limitless proliferation. Here, we uncover two distinct mechanisms by which naturally occurring oxidized dNTPs and therapeutic dNTPs inhibit telomerase-mediated telomere elongation. We conduct a series of direct telomerase extension assays in the presence of modified dNTPs on various telomeric substrates. We provide direct evidence that telomerase can add the nucleotide reverse transcriptase inhibitors ddITP and AZT-TP to the telomeric end, causing chain termination. In contrast, telomerase continues elongation after inserting oxidized 2-OH-dATP or therapeutic 6-thio-dGTP, but insertion disrupts translocation and inhibits further repeat addition. Kinetics reveal that telomerase poorly selects against 6-thio-dGTP, inserting with similar catalytic efficiency as dGTP. Furthermore, telomerase processivity factor POT1-TPP1 fails to restore processive elongation in the presence of inhibitory dNTPs. These findings reveal mechanisms for targeting telomerase with modified dNTPs in cancer therapy.
Observation of magneto-electric rectification at non-relativistic intensities
Authors: Trinh M. Tuan , Smail Gregory , Makhal Krishnandu , Yang Da Seul , Kim Jinsang , Rand Stephen C.
Published: October 2020

The subject of electromagnetism has often been called electrodynamics to emphasize the dominance of the electric field in dynamic light–matter interactions that take place under non-relativistic conditions. Here we show experimentally that the often neglected optical magnetic field can nevertheless play an important role in a class of optical nonlinearities driven by both the electric and magnetic components of light at modest (non-relativistic) intensities. We specifically report the observation of magneto-electric rectification, a previously unexplored nonlinearity at the molecular level which has important potential for energy conversion, ultrafast switching, nano-photonics, and nonlinear optics. Our experiments were carried out in nanocrystalline pentacene thin films possessing spatial inversion symmetry that prohibited second-order, all-electric nonlinearities but allowed magneto-electric rectification.
Optical beaming of electrical discharges
Authors: Shvedov V. , Pivnev E. , Davoyan A. R. , Krolikowski W. , Miroshnichenko A. E.
Published: October 2020

Igniting and guiding electrical discharges to desired targets in the ambient atmosphere have been a subject of intense research efforts for decades. Ability to control discharge and its propagation can pave the way to a broad range of applications from nanofabrication and plasma medicine to monitoring of atmospheric pollution and, ultimately, taming lightning strikes. Numerous experiments utilizing powerful pulsed lasers with peak-intensity above air photoionization and photo-dissociation have demonstrated excitation and confinement of plasma tracks in the wakes of laser field. Here, we propose and demonstrate an efficient approach for triggering, trapping and guiding electrical discharges in air. It is based on the use of a low-power continuous-wave vortex beam that traps and transports light-absorbing particles in mid-air. We demonstrate a 30% decrease in discharge threshold mediated by optically trapped graphene microparticles with the use of a laser beam of a few hundred milliwatts of power. Our demonstration may pave the way to guiding electrical discharges along arbitrary paths.
Inhaled corticosteroids and the risk of type 2 diabetes among Swedish COPD patients
Authors: Ställberg Björn , Janson Christer , Lisspers Karin , Johansson Gunnar , Gutzwiller Florian S. , Mezzi Karen , Bjerregaard Bine Kjoeller , Kejs Anne Mette Tranberg , Jorgensen Leif , Larsson Kjell
Published: October 2020

This study reports the association of ICS use and the risk of type 2 diabetes mellitus (T2DM) in Swedish patients with COPD using data from real-world, primary care settings. A total of 7078 patients with COPD were included in this analysis and the 5-year cumulative incidence rate per 100,000 person years was 1506.9. The yearly incidence rate per 100,000 person years ranged from 850 to 1919. Use of ICS especially at a high dose in patients with COPD was related to an increased risk of T2DM.
Publisher Correction: Implementing a context-driven awareness programme addressing household air pollution and tobacco: a FRESH AIR study
Authors: Brakema Evelyn A. , van Gemert Frederik A. , Williams Sian , Sooronbaev Talant , Emilov Berik , Mademilov Maamed , Tabyshova Aizhamal , Le An Pham , Quynh Nguyen Nhat , Hong Le Huynh Thi Cam , Dang Tran Ngoc , van der Kleij Rianne M. J. J. , Chavannes Niels H. , de Jong Corina ,   The FRESH AIR collaborators, Anastasaki Marilena , Akylbekov Azamat , Barton Andy , Bertsias Antonios , Binh Pham Duong Uyen , van Boven Job F. M. , Burges Dennis , Cartwright Lucy , Chatzea Vasiliki E. , Cragg Liza , Dautov Ilyas , Ferarrio Irene , Hedrick Ben , Hopkinson Nick , Isaeva Elvira , Jones Rupert , van Kampen Sanne , Katagira Winceslaus , Kjærgaard Jesper , Kocks Janwillem , Lan Le Thi Tuyet , Linh Tran Thanh Duv , Lionis Christos , Loan Kim Xuan , McEwen Andy , Musinguzi Patrick , Nantanda Rebecca , Ndeezi Grace , Papadakis Sophia , Pinnock Hilary , Pooler Jillian , Poot Charlotte C. , Postma Maarten J. , Poulsen Anja , Powell Pippa , Reventlow Susanne , Sifaki-Pistolla Dimitra , Singh Sally , de Sousa Jaime Correia , Stout James , Østergaard Marianne Stubbe , Tsiligianni Ioanna , Tuan Tran Diep , Tumwine James , Van Le Thanh , Vinh Nguyen Nhu , Walusimbi Simon , Warren Louise
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Draft genome of Bugula neritina, a colonial animal packing powerful symbionts and potential medicines
Authors: Rayko Mikhail , Komissarov Aleksey , Kwan Jason C. , Lim-Fong Grace , Rhodes Adelaide C. , Kliver Sergey , Kuchur Polina , O’Brien Stephen J. , Lopez Jose V.
Published: October 2020

Many animal phyla have no representatives within the catalog of whole metazoan genome sequences. This dataset fills in one gap in the genome knowledge of animal phyla with a draft genome of Bugula neritina (phylum Bryozoa). Interest in this species spans ecology and biomedical sciences becauseB. neritinais the natural source of bioactive compounds called bryostatins. Here we present a draft assembly of theB. neritinagenome obtained from PacBio and Illumina HiSeq data, as well as genes and proteins predicted de novo and verified using transcriptome data, along with the functional annotation. These sequences will permit a better understanding of host-symbiont interactions at the genomic level, and also contribute additional phylogenomic markers to evaluate Lophophorate or Lophotrochozoa phylogenetic relationships. The effort also fits well with plans to ultimately sequence all orders of the Metazoa.
Ab initio study for molecular-scale adsorption, decomposition and desorption on AlN surfaces during MOCVD growth
Authors: An Jiadai , Dai Xianying , Guo Runqiu , Feng Lansheng , Zhao Tianlong
Published: October 2020

Since AlGaN offers new opportunities for the development of the solid state ultraviolet (UV) luminescence, detectors and high-power electronic devices, the growth of AlN buffer substrate is concerned. However, the growth of AlN buffer substrate during MOCVD is regulated by an intricate interplay of gas-phase and surface reactions that are beyond the resolution of experimental techniques, especially the surface growth process. We used density-functional ab initio calculations to analyze the adsorption, decomposition and desorption of group-III and group-V sources on AlN surfaces during MOCVD growth in molecular-scale. For AlCH3 molecule the group-III source, the results indicate that AlCH3 is more easily adsorbed on AlN (0001) than (000$$\overline{1}$$

1
¯

) surface on the top site. For the group-V source decomposition we found that NH2 molecule is the most favorable adsorption source and adsorbed on the top site. We investigated the adsorption of group-III source on the reconstructed AlN (0001) surface which demonstrates that NH2-rich condition has a repulsion effect to it. Furthermore, the desorption path of group-III and group-V radicals has been proposed. Our study explained the molecular-scale surface reaction mechanism of AlN during MOCVD and established the surface growth model on AlN (0001) surface.
A putative chordate luciferase from a cosmopolitan tunicate indicates convergent bioluminescence evolution across phyla
Authors: Tessler Michael , Gaffney Jean P. , Oliveira Anderson G. , Guarnaccia Andrew , Dobi Krista C. , Gujarati Nehaben A. , Galbraith Moira , Mirza Jeremy D. , Sparks John S. , Pieribone Vincent A. , Wood Robert J. , Gruber David F.
Published: October 2020

Pyrosomes are tunicates in the phylum Chordata, which also contains vertebrates. Their gigantic blooms play important ecological and biogeochemical roles in oceans.Pyrosoma, meaning “fire-body”, derives from their brilliant bioluminescence. The biochemistry of this light production is unknown, but has been hypothesized to be bacterial in origin. We found that mixing coelenterazine—a eukaryote-specific luciferin—withPyrosoma atlanticumhomogenate produced light. To identify the bioluminescent machinery, we sequencedP. atlanticumtranscriptomes and found a sequence match to a cnidarian luciferase (RLuc). We expressed this novel luciferase (PyroLuc) and, combined with coelenterazine, it produced light. A similar gene was recently predicted from a bioluminescent brittle star, indicating that RLuc-like luciferases may have evolved convergently from homologous dehalogenases across phyla (Cnidaria, Echinodermata, and Chordata). This report indicates that a widespread gene may be able to functionally converge, resulting in bioluminescence across animal phyla, and describes and characterizes the first putative chordate luciferase.
Real-life experience with 4 years of golimumab persistence in ulcerative colitis patients
Authors: Iborra Marisa , García-Morales Natalia , Rubio Saoia , Bertoletti Federico , Calvo Marta , Taxonera Carlos , Boscá-Watts Marta Maia , Sierra Mónica , Mancenido Noemí , Beltrán Belén , Nantes Castillejo Óscar , García-Planella Esther , Vera Isabel , Alba Cristina , Martí-Aguado David , Ballester María Pilar , Cano-Sanz Noelia , Pajares-Villarroya Ramón , Cerrillo Elena , Cañada Antonio , Nos Pilar
Published: October 2020

Golimumab has demonstrated its long-term efficacy and safety in ulcerative colitis in clinical trials, but no data of long-term persistence has been published from real world. To estimate long-term persistence of golimumab, as well as factors associated with longer persistence, in patients with ulcerative colitis in real life. Observational multicentre study including adult patients with ulcerative colitis treated with golimumab and with at least twelve months of follow-up. We included 190 patients, 105 (55.26%) naive to anti-TNF, with mean disease duration of 9.32 ± 8.09 years. Probability of persistence was 63%, 46%, 39% and 27% at 1, 2, 3 and 4 years, respectively. Persistence was lower in patients with primary failure to previous anti-TNF. Eighty-two (43.16%) patients needed dose intensification during follow-up, with a mean time until intensification of 8.03 ± 8.64 months. Dose intensification and lower disease duration predicted higher persistence with golimumab (p = 0.037 and p = 0.008, respectively). During a follow-up of 17.25 ± 15.83 months, 32 (16.5%) patients needed hospitalisation and 11 (6%) underwent colectomy. No unexpected adverse events were reported. Golimumab has demonstrated good persistence and safety profile for long treatment in ulcerative colitis patients.
Evaluation of the impact of heat on wheat dormancy, late maturity α-amylase and grain size under controlled conditions in diverse germplasm
Authors: Barrero Jose M. , Porfirio Luciana , Hughes Trijntje , Chen Jing , Dillon Shannon , Gubler Frank , Ral Jean-Philippe F.
Published: October 2020

In the Australian wheat belts, short episodes of high temperatures or hot spells during grain filling are becoming increasingly common and have an enormous impact on yield and quality, bringing multi-billion losses annually. This problem will become recurrent under the climate change scenario that forecast increasing extreme temperatures, but so far, no systematic analysis of the resistance to hot spells has yet been performed in a diverse genetic background. We developed a protocol to study the effects of heat on three important traits: grain size, grain dormancy and the presence of Late Maturity α-Amylase (LMA), and we validated it by analysing the phenotypes of 28 genetically diverse wheat landraces and exploring the potential variability existing in the responses to hot spells. Using controlled growth environments, the different genotypes were grown in our standard conditions until 20 days after anthesis, and then moved for 10 days into a heat chamber. Our study showed that our elevated temperature treatment during mid-late filling triggered multiple detrimental effects on yield and quality. We observed a reduction in grain size, a reduction in grain dormancy and increased LMA expression in most of the tested genotypes, but potential resistant lines were identified for each analyzed trait opening new perspectives for future genetic studies and breeding for heat-insensitive commercial lines.