bluuebunny/crossref_metadata_2025 huggingface dataset:
Melanoma recurrence patterns and management after adjuvant targeted therapy: a multicentre analysis
Authors: Bhave Prachi , Pallan Lalit , Long Georgina V. , Menzies Alexander M. , Atkinson Victoria , Cohen Justine V. , Sullivan Ryan J. , Chiarion-Sileni Vanna , Nyakas Marta , Kahler Katharina , Hauschild Axel , Plummer Ruth , Trojaniello Claudia , Ascierto Paolo A. , Zimmer Lisa , Schadendorf Dirk , Allayous Clara , Lebbe Celeste , Maurichi Andrea , Santinami Mario , Roy Severine , Robert Caroline , Lesimple Thierry , Patel Sapna , Versluis Judith M. , Blank Christian U. , Khattak Adnan , Van der Westhuizen Andre , Carlino Matteo S. , Shackleton Mark , Haydon Andrew
Published: October 2020

Background

Adjuvant targeted therapy (TT) improves relapse free survival in patients with resected BRAF mutant stage III melanoma. The outcomes and optimal management of patients who relapse after adjuvant TT is unknown.

Methods

Patients from twenty-one centres with recurrent melanoma after adjuvant TT were included. Disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcomes were examined.

Results

Eighty-five patients developed recurrent melanoma; nineteen (22%) during adjuvant TT. Median time to first recurrence was 18 months and median follow-up from first recurrence was 31 months. Fifty-eight (68%) patients received immunotherapy (IT) or TT as 1st line systemic therapy at either first or subsequent recurrence and had disease that was assessable for response. Response to anti-PD-1 (±trial agent), combination ipilimumab-nivolumab, TT rechallenge and ipilimumab monotherapy was 63%, 62% 25% and 10% respectively. Twenty-eight (33%) patients had died at census, all from melanoma. Two-year OS was 84% for anti-PD-1 therapy (±trial agent), 92% for combination ipilimumab and nivolumab, 49% for TT and 45% for ipilimumab monotherapy (p = 0.028).

Conclusions

Patients who relapse after adjuvant TT respond well to subsequent anti-PD-1 based therapy and have outcomes similar to those seen when first line anti-PD-1 therapy is used in stage IV melanoma.
miR-322/-503 rescues myoblast defects in myotonic dystrophy type 1 cell model by targeting CUG repeats
Authors: Shen Xiaopeng , Xu Feng , Li Meng , Wu Shen , Zhang Jingyi , Wang Ao , Xu Lei , Liu Yu , Zhu Guoping
Published: October 2020

Myotonic dystrophy type 1 (DM1) is the most common type of adult muscular dystrophy caused by the expanded triple-nucleotides (CUG) repeats. Myoblast in DM1 displayed many defects, including defective myoblast differentiation, ribonuclear foci, and aberrant alternative splicing. Despite many were revealed to function in DM1, microRNAs that regulated DM1 via directly targeting the expanded CUG repeats were rarely reported. Here we discovered that miR-322/-503 rescued myoblast defects in DM1 cell model by targeting the expanded CUG repeats. First, we studied the function of miR-322/-503 in normal C2C12 myoblast cells. Downregulation of miR-322/-503 significantly hindered the myoblast differentiation, while miR-322/-503 overexpression promoted the process. Next, we examined the role of miR-322/-503 in the DM1 C2C12 cell model. miR-322/-503 was downregulated in the differentiation of DM1 C2C12 cells. When we introduced ectopic miR-322/-503 expression into DM1 C2C12 cells, myoblast defects were almost fully rescued, marked by significant improvements of myoblast differentiation and repressions of ribonuclear foci formation and aberrant alternative splicing. Then we investigated the downstream mechanism of miR-322/-503 in DM1. Agreeing with our previous work, Celf1 was proven to be miR-322/-503′s target. Celf1 knockdown partially reproduced miR-322/-503′s function in rescuing DM1 C2C12 differentiation but was unable to repress ribonuclear foci, suggesting other targets of miR-322/-503 existed in the DM1 C2C12 cells. As the seed regions of miR-322 and miR-503 were complementary to the CUG repeats, we hypothesized that the CUG repeats were the target of miR-322/-503. Through expression tests, reporter assays, and colocalization staining, miR-322/-503 was proved to directly and specifically target the expanded CUG repeats in the DM1 cell model rather than the shorter ones in normal cells. Those results implied a potential therapeutic function of miR-322/-503 on DM1, which needed further investigations in the future.
Aggresome formation and liquid–liquid phase separation independently induce cytoplasmic aggregation of TAR DNA-binding protein 43
Authors: Watanabe Seiji , Inami Hidekazu , Oiwa Kotaro , Murata Yuri , Sakai Shohei , Komine Okiru , Sobue Akira , Iguchi Yohei , Katsuno Masahisa , Yamanaka Koji
Published: October 2020

Cytoplasmic inclusion of TAR DNA-binding protein 43 (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and a subtype of frontotemporal lobar degeneration (FTLD). Recent studies have suggested that the formation of cytoplasmic TDP-43 aggregates is dependent on a liquid–liquid phase separation (LLPS) mechanism. However, it is unclear whether TDP-43 pathology is induced through a single intracellular mechanism such as LLPS. To identify intracellular mechanisms responsible for TDP-43 aggregation, we established a TDP-43 aggregation screening system using a cultured neuronal cell line stably expressing EGFP-fused TDP-43 and a mammalian expression library of the inherited ALS/FTLD causative genes, and performed a screening. We found that microtubule-related proteins (MRPs) and RNA-binding proteins (RBPs) co-aggregated with TDP-43. MRPs and RBPs sequestered TDP-43 into the cytoplasmic aggregates through distinct mechanisms, such as microtubules and LLPS, respectively. The MRPs-induced TDP-43 aggregates were co-localized with aggresomal markers and dependent on histone deacetylase 6 (HDAC6), suggesting that aggresome formation induced the co-aggregation. However, the MRPs-induced aggregates were not affected by 1,6-hexanediol, an LLPS inhibitor. On the other hand, the RBPs-induced TDP-43 aggregates were sensitive to 1,6-hexanediol, but not dependent on microtubules or HDAC6. In sporadic ALS patients, approximately half of skein-like TDP-43 inclusions were co-localized with HDAC6, but round and granular type inclusion were not. Moreover, HDAC6-positive and HDAC6-negative inclusions were found in the same ALS patient, suggesting that the two distinct pathways are both involved in TDP-43 pathology. Our findings suggest that at least two distinct pathways (i.e., aggresome formation and LLPS) are involved in inducing the TDP-43 pathologies.
Flexible transparent heteroepitaxial conducting oxide with mobility exceeding 100 cm2 V−1 s−1 at room temperature
Authors: Ma Chun-Hao , Chen En-Liang , Lai Yu-Hong , Chen Yi-Cheng , Chang Li , Chu Ying-Hao
Published: October 2020

Flexible and transparent applications have become an emerging technology and have shifted to the forefront of materials science research in recent years. Transparent conductive oxide films have been applied for flat panel displays, solar cells, and transparent glass coatings. However, none of them can fulfill the requirements for advanced transparent flexible devices, such as high-frequency applications. Here, we present a promising technique for transparent flexible conducting oxide heteroepitaxial films: the direct fabrication of epitaxial molybdenum-doped indium oxide (IMO) thin films on a transparent flexible muscovite substrate. An n-type epitaxial IMO film is demonstrated with a mobility of 109 cm2 V−1 s−1, a figure of merit of 0.0976 Ω−1, a resistivity of 4.5 × 10−5 Ω cm and an average optical transmittance of 81.8% in the visible regime. This heteroepitaxial system not only exhibits excellent electrical and optical performance but also shows excellent mechanical durability. Our results illustrate that this is an outstanding way to fabricate transparent and flexible conducting elements for the evolution and expansion of next-generation smart devices.
Long-range phase synchronization of high-frequency oscillations in human cortex
Authors: Arnulfo G. , Wang S. H. , Myrov V. , Toselli B. , Hirvonen J. , Fato M. M. , Nobili L. , Cardinale F. , Rubino A. , Zhigalov A. , Palva S. , Palva J. M.
Published: October 2020

Inter-areal synchronization of neuronal oscillations at frequencies below ~100 Hz is a pervasive feature of neuronal activity and is thought to regulate communication in neuronal circuits. In contrast, faster activities and oscillations have been considered to be largely local-circuit-level phenomena without large-scale synchronization between brain regions. We show, using human intracerebral recordings, that 100–400 Hz high-frequency oscillations (HFOs) may be synchronized between widely distributed brain regions. HFO synchronization expresses individual frequency peaks and exhibits reliable connectivity patterns that show stable community structuring. HFO synchronization is also characterized by a laminar profile opposite to that of lower frequencies. Importantly, HFO synchronization is both transiently enhanced and suppressed in separate frequency bands during a response-inhibition task. These findings show that HFO synchronization constitutes a functionally significant form of neuronal spike-timing relationships in brain activity and thus a mesoscopic indication of neuronal communication per se.
Type III ATP synthase is a symmetry-deviated dimer that induces membrane curvature through tetramerization
Authors: Flygaard Rasmus Kock , Mühleip Alexander , Tobiasson Victor , Amunts Alexey
Published: October 2020

Mitochondrial ATP synthases form functional homodimers to induce cristae curvature that is a universal property of mitochondria. To expand on the understanding of this fundamental phenomenon, we characterized the unique type III mitochondrial ATP synthase in its dimeric and tetrameric form. The cryo-EM structure of a ciliate ATP synthase dimer reveals an unusual U-shaped assembly of 81 proteins, including a substoichiometrically bound ATPTT2, 40 lipids, and co-factors NAD and CoQ. A single copy of subunit ATPTT2 functions as a membrane anchor for the dimeric inhibitor IF1. Type III specific linker proteins stably tie the ATP synthase monomers in parallel to each other. The intricate dimer architecture is scaffolded by an extended subunit-a that provides a template for both intra- and inter-dimer interactions. The latter results in the formation of tetramer assemblies, the membrane part of which we determined to 3.1 Å resolution. The structure of the type III ATP synthase tetramer and its associated lipids suggests that it is the intact unit propagating the membrane curvature.
Social attraction in Drosophila is regulated by the mushroom body and serotonergic system
Authors: Sun Yuanjie , Qiu Rong , Li Xiaonan , Cheng Yaxin , Gao Shan , Kong Fanchen , Liu Li , Zhu Yan
Published: October 2020

Sociality is among the most important motivators of human behaviour. However, the neural mechanisms determining levels of sociality are largely unknown, primarily due to a lack of suitable animal models. Here, we report the presence of a surprising degree of general sociality in Drosophila. A newly-developed paradigm to study social approach behaviour in flies reveal that social cues perceive through both vision and olfaction converged in a central brain region, the γ lobe of the mushroom body, which exhibite activation in response to social experience. The activity of these γ neurons control the motivational drive for social interaction. At the molecular level, the serotonergic system is critical for social affinity. These results demonstrate that Drosophila are highly sociable, providing a suitable model system for elucidating the mechanisms underlying the motivation for sociality.
Formation and diversification of a paradigm biosynthetic gene cluster in plants
Authors: Liu Zhenhua , Cheema Jitender , Vigouroux Marielle , Hill Lionel , Reed James , Paajanen Pirita , Yant Levi , Osbourn Anne
Published: October 2020

Numerous examples of biosynthetic gene clusters (BGCs), including for compounds of agricultural and medicinal importance, have now been discovered in plant genomes. However, little is known about how these complex traits are assembled and diversified. Here, we examine a large number of variants within and between species for a paradigm BGC (the thalianol cluster), which has evolved recently in a common ancestor of the Arabidopsis genus. Comparisons at the species level reveal differences in BGC organization and involvement of auxiliary genes, resulting in production of species-specific triterpenes. Within species, the thalianol cluster is primarily fixed, showing a low frequency of deleterious haplotypes. We further identify chromosomal inversion as a molecular mechanism that may shuffle more distant genes into the cluster, so enabling cluster compaction. Antagonistic natural selection pressures are likely involved in shaping the occurrence and maintenance of this BGC. Our work sheds light on the birth, life and death of complex genetic and metabolic traits in plants.
Dramatic uneven urbanization of large cities throughout the world in recent decades
Authors: Sun Liqun , Chen Ji , Li Qinglan , Huang Dian
Published: October 2020

The world has experienced dramatic urbanization in recent decades. However, we still lack information about the characteristics of urbanization in large cities throughout the world. After analyzing 841 large cities with built-up areas (BUAs) of over 100 km2 from 2001 to 2018, here we found an uneven distribution of urbanization at different economic levels. On average, large cities in the low-income and lower-middle-income countries had the highest urban population growth, and BUA expansion in the upper-middle-income countries was more than three times that of the high-income countries. Globally, more than 10% of BUAs in 325 large cities showed significant greening (P < 0.05) from 2001 to 2018. In particular, China accounted for 32% of greening BUAs in the 841 large cities, where about 108 million people lived. Our quantitative results provide information for future urban sustainable development, especially for rational urbanization of the developing world.
Brainstem development requires galactosylceramidase and is critical for pathogenesis in a model of Krabbe disease
Authors: Weinstock Nadav I. , Kreher Conlan , Favret Jacob , Nguyen Duc , Bongarzone Ernesto R. , Wrabetz Lawrence , Feltri M. Laura , Shin Daesung
Published: October 2020

Krabbe disease (KD) is caused by a deficiency of galactosylceramidase (GALC), which induces demyelination and neurodegeneration due to accumulation of cytotoxic psychosine. Hematopoietic stem cell transplantation (HSCT) improves clinical outcomes in KD patients only if delivered pre-symptomatically. Here, we hypothesize that the restricted temporal efficacy of HSCT reflects a requirement for GALC in early brain development. Using a novel Galc floxed allele, we induce ubiquitous GALC ablation (Galc-iKO) at various postnatal timepoints and identify a critical period of vulnerability to GALC ablation between P4-6 in mice. Early Galc-iKO induction causes a worse KD phenotype, higher psychosine levels in the rodent brainstem and spinal cord, and a significantly shorter life-span of the mice. Intriguingly, GALC expression peaks during this critical developmental period in mice. Further analysis of this mouse model reveals a cell autonomous role for GALC in the development and maturation of immature T-box-brain-1 positive brainstem neurons. These data identify a perinatal developmental period, in which neuronal GALC expression influences brainstem development that is critical for KD pathogenesis.
The seventh pandemic of cholera in Europe revisited by microbial genomics
Authors: Oprea Mihaela , Njamkepo Elisabeth , Cristea Daniela , Zhukova Anna , Clark Clifford G. , Kravetz Anatoly N. , Monakhova Elena , Ciontea Adriana S. , Cojocaru Radu , Rauzier Jean , Damian Maria , Gascuel Olivier , Quilici Marie-Laure , Weill François-Xavier
Published: October 2020

In 1970, the seventh pandemic of cholera (7 P) reached both Africa and Europe. Between 1970 and 2011, several European countries reported cholera outbreaks of a few to more than 2,000 cases. We report here a whole-genome analysis of 1,324 7 P V. cholerae El Tor (7 PET) isolates, including 172 from autochthonous sporadic or outbreak cholera cases occurring between 1970 and 2011 in Europe, providing insight into the spatial and temporal spread of this pathogen across Europe. In this work, we show that the 7 PET lineage was introduced at least eight times into two main regions: Eastern and Southern Europe. Greater recurrence of the disease was observed in Eastern Europe, where it persisted until 2011. It was introduced into this region from Southern Asia, often circulating regionally in the countries bordering the Black Sea, and in the Middle East before reaching Eastern Africa on several occasions. In Southern Europe, the disease was mostly seen in individual countries during the 1970s and was imported from North and West Africa, except in 1994, when cholera was imported into Albania and Italy from the Black Sea region. These results shed light on the geographic course of cholera during the seventh pandemic and highlight the role of humans in its global dissemination.
Dopants fixation of Ruthenium for boosting acidic oxygen evolution stability and activity
Authors: Hao Shaoyun , Liu Min , Pan Junjie , Liu Xiangnan , Tan Xiaoli , Xu Nan , He Yi , Lei Lecheng , Zhang Xingwang
Published: October 2020

Designing highly durable and active electrocatalysts applied in polymer electrolyte membrane (PEM) electrolyzer for the oxygen evolution reaction remains a grand challenge due to the high dissolution of catalysts in acidic electrolyte. Hindering formation of oxygen vacancies by tuning the electronic structure of catalysts to improve the durability and activity in acidic electrolyte was theoretically effective but rarely reported. Herein we demonstrated rationally tuning electronic structure of RuO2 with introducing W and Er, which significantly increased oxygen vacancy formation energy. The representative W0.2Er0.1Ru0.7O2-δ required a super-low overpotential of 168 mV (10 mA cm−2) accompanied with a record stability of 500 h in acidic electrolyte. More remarkably, it could operate steadily for 120 h (100 mA cm−2) in PEM device. Density functional theory calculations revealed co-doping of W and Er tuned electronic structure of RuO2 by charge redistribution, which significantly prohibited formation of soluble Rux>4 and lowered adsorption energies for oxygen intermediates.
Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer’s disease
Authors: McQuade Amanda , Kang You Jung , Hasselmann Jonathan , Jairaman Amit , Sotelo Alexandra , Coburn Morgan , Shabestari Sepideh Kiani , Chadarevian Jean Paul , Fote Gianna , Tu Christina H. , Danhash Emma , Silva Jorge , Martinez Eric , Cotman Carl , Prieto G. Aleph , Thompson Leslie M. , Steffan Joan S. , Smith Ian , Davtyan Hayk , Cahalan Michael , Cho Hansang , Blurton-Jones Mathew
Published: October 2020

The discovery of TREM2 as a myeloid-specific Alzheimer’s disease (AD) risk gene has accelerated research into the role of microglia in AD. While TREM2 mouse models have provided critical insight, the normal and disease-associated functions of TREM2 in human microglia remain unclear. To examine this question, we profile microglia differentiated from isogenic, CRISPR-modified TREM2-knockout induced pluripotent stem cell (iPSC) lines. By combining transcriptomic and functional analyses with a chimeric AD mouse model, we find that TREM2 deletion reduces microglial survival, impairs phagocytosis of key substrates including APOE, and inhibits SDF-1α/CXCR4-mediated chemotaxis, culminating in an impaired response to beta-amyloid plaques in vivo. Single-cell sequencing of xenotransplanted human microglia further highlights a loss of disease-associated microglial (DAM) responses in human TREM2 knockout microglia that we validate by flow cytometry and immunohistochemistry. Taken together, these studies reveal both conserved and novel aspects of human TREM2 biology that likely play critical roles in the development and progression of AD.
Author Correction: Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing
Authors: Maule Giulia , Casini Antonio , Montagna Claudia , Ramalho Anabela S. , De Boeck Kris , Debyser Zeger , Carlon Marianne S. , Petris Gianluca , Cereseto Anna
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Author Correction: A consensus S. cerevisiae metabolic model Yeast8 and its ecosystem for comprehensively probing cellular metabolism
Authors: Lu Hongzhong , Li Feiran , Sánchez Benjamín J. , Zhu Zhengming , Li Gang , Domenzain Iván , Marcišauskas Simonas , Anton Petre Mihail , Lappa Dimitra , Lieven Christian , Beber Moritz Emanuel , Sonnenschein Nikolaus , Kerkhoven Eduard J. , Nielsen Jens
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Navigating facilitated regulatory pathways during a disease X pandemic
Authors: Simpson Shmona , Chakrabarti Ajoy , Robinson David , Chirgwin Keith , Lumpkin Murray
Published: October 2020

In 2018, the Bill and Melinda Gates Foundation convened over thirty subject matter experts in clinical development, manufacturing, and regulatory assessment to determine how the development and approval of medical countermeasures could be accelerated in the event of Disease X. Disease X is the result of a presently unknown pathogen with epidemic or pandemic potential. A key opportunity to accelerate the scientific assessment and regulatory approval of medical countermeasures exists within efficient navigation of facilitated regulatory pathways. It was identified that not all stakeholders will be able to skillfully navigate the facilitated pathways offered by the various regulatory agencies during a public health emergency. To democratize this knowledge, we have written an overview of the facilitated approaches which have been developed and refined by Stringent Regulatory Authorities and the World Health Organization for the primary assessment of medical products. We discuss the conditions necessary for use of these approaches, scenarios in which certain pathways may be applicable, and the pros and cons of these approaches. We also address opportunities available to developers in, or developers who wish to access, low-income countries that may have nascent regulatory frameworks.
Metagenomic characterization of bacterial community and antibiotic resistance genes in representative ready-to-eat food in southern China
Authors: Li YiMing , Cao WeiWei , Liang ShuLi , Yamasaki Shinji , Chen Xun , Shi Lei , Ye Lei
Published: October 2020

Ready-to-eat (RTE) foods have been considered to be reservoirs of antibiotic resistance bacteria, which constitute direct threat to human health, but the potential microbiological risks of RTE foods remain largely unexplored. In this study, the metagenomic approach was employed to characterize the comprehensive profiles of bacterial community and antibiotic resistance gene (ARG) in 18 RTE food samples (8 RTE meat, 7 RTE vegetables and 3 RTE fruit) in southern China. In total, the most abundant phyla in RTE foods were Proteobacteria, Firmicutes, Cyanobacteria, Bacteroidetes and Actinobacteria. 204 ARG subtypes belonging to 18 ARG types were detected with an abundance range between 2.81 × 10−5 and 7.7 × 10−1 copy of ARG per copy of 16S rRNA gene. Multidrug-resistant genes were the most predominant ARG type in the RTE foods. Chloramphenicol, macrolide-lincosamide-streptogramin, multidrug resistance, aminoglycoside, bacitracin, tetracycline and β-lactam resistance genes were dominant, which were also associated with antibiotics used extensively in human medicine or veterinary medicine/promoters. Variation partitioning analysis indicated that the join effect of bacterial community and mobile genetic elements (MGEs) played an important role in the resistome alteration. This study further deepens the comprehensive understanding of antibiotic resistome and the correlations among the antibiotic resistome, microbiota, and MGEs in the RTE foods.
Therapeutic effect of Aegle marmelos fruit extract against DMBA induced breast cancer in rats
Authors: Akhouri Vivek , Kumari Manorma , Kumar Arun
Published: October 2020

Breast cancer is among most common form of cancer worldwide. It is also the major cause of death in female cancer patient around the world. Despite various therapeutic measures, it remains associated with high mortality rate. Aegle marmelos (L.) Correa has been extensively used in Indian medicine system Ayurveda, due to its various medicinal properties. However, there are very limited reports regarding its anticancer activity. Thus, the present research work has been aimed to study the anticancer activity of Aegle marmelos fruit extract on 7,12-dimethylbenz(a)anthracene (DMBA) induced breast cancer in rats. Female Charles Foster rats, 55–60 days old weighing around (150 ± 10 g) were used for the study and were induced DMBA (20 mg/mL dissolved in Olive oil) orally. After the development of breast tumors (about 0.5 cm), the rats were treated with Aegle marmelos ethanolic fruit pulp extract (200 mg/kg b.w./day) orally for 5 weeks and then volume of tumor was measured. Aegle marmelos treatment showed significantly reduced mammary tumor volume (P < 0.05), along with significant reduction (P < 0.0001) in the different serum biomarkers such as TNF-α level, serum malondialdehyde (MDA) level and glucose levels. Significant (P < 0.0001) improvement in both, the kidney and liver serum biomarker parameters were also observed after the treatment with Aegle marmelos ethanolic fruit pulp extract. From the entire study, taking everything into account it can be interpreted that Aegle marmelos ethanolic fruit pulp extract possesses anti-proliferative activity by suppressing the progression of breast tumors in rat model. The plant extract also possesses hepato-renal protective effect. Hence, it can be targeted as novel and safe anti-cancer drug against breast cancer.
Application of artificial neural network for predicting the performance of CO2 enhanced oil recovery and storage in residual oil zones
Authors: Vo Thanh Hung , Sugai Yuichi , Sasaki Kyuro
Published: October 2020

Residual Oil Zones (ROZs) become potential formations for Carbon Capture, Utilization, and Storage (CCUS). Although the growing attention in ROZs, there is a lack of studies to propose the fast tool for evaluating the performance of a CO2 injection process. In this paper, we introduce the application of artificial neural network (ANN) for predicting the oil recovery and CO2 storage capacity in ROZs. The uncertainties parameters, including the geological factors and well operations, were used for generating the training database. Then, a total of 351 numerical samples were simulated and created the Cumulative oil production, Cumulative CO2 storage, and Cumulative CO2 retained. The results indicated that the developed ANN model had an excellent prediction performance with a high correlation coefficient (R2) was over 0.98 on comparing with objective values, and the total root mean square error of less than 2%. Also, the accuracy and stability of ANN models were validated for five real ROZs in the Permian Basin. The predictive results were an excellent agreement between ANN predictions and field report data. These results indicated that the ANN model could predict the CO2 storage and oil recovery with high accuracy, and it can be applied as a robust tool to determine the feasibility in the early stage of CCUS in ROZs. Finally, the prospective application of the developed ANN model was assessed by optimization CO2-EOR and storage projects. The developed ANN models reduced the computational time for the optimization process in ROZs.
Distribution of genetic diversity reveals colonization patterns and philopatry of the loggerhead sea turtles across geographic scales
Authors: Baltazar-Soares Miguel , Klein Juliana D. , Correia Sandra M. , Reischig Thomas , Taxonera Albert , Roque Silvana Monteiro , Dos Passos Leno , Durão Jandira , Lomba João Pina , Dinis Herculano , Cameron Sahmorie J.K. , Stiebens Victor A. , Eizaguirre Christophe
Published: October 2020

Understanding the processes that underlie the current distribution of genetic diversity in endangered species is a goal of modern conservation biology. Specifically, the role of colonization and dispersal events throughout a species’ evolutionary history often remains elusive. The loggerhead sea turtle (Caretta caretta) faces multiple conservation challenges due to its migratory nature and philopatric behaviour. Here, using 4207 mtDNA sequences, we analysed the colonisation patterns and distribution of genetic diversity within a major ocean basin (the Atlantic), a regional rookery (Cabo Verde Archipelago) and a local island (Island of Boa Vista, Cabo Verde). Data analysis using hypothesis-driven population genetic models suggests the colonization of the Atlantic has occurred in two distinct waves, each corresponding to a major mtDNA lineage. We propose the oldest lineage entered the basin via the isthmus of Panama and sequentially established aggregations in Brazil, Cabo Verde and in the area of USA and Mexico. The second lineage entered the Atlantic via the Cape of Good Hope, establishing colonies in the Mediterranean Sea, and from then on, re-colonized the already existing rookeries of the Atlantic. At the Cabo Verde level, we reveal an asymmetric gene flow maintaining links across island-specific nesting groups, despite significant genetic structure. This structure stems from female philopatric behaviours, which could further be detected by weak but significant differentiation amongst beaches separated by only a few kilometres on the island of Boa Vista. Exploring biogeographic processes at diverse geographic scales improves our understanding of the complex evolutionary history of highly migratory philopatric species. Unveiling the past facilitates the design of conservation programmes targeting the right management scale to maintain a species’ evolutionary potential.
Median preoptic area neurons are required for the cooling and febrile activations of brown adipose tissue thermogenesis in rat
Authors: da Conceição Ellen Paula Santos , Morrison Shaun F. , Cano Georgina , Chiavetta Pierfrancesco , Tupone Domenico
Published: October 2020

Within the central neural circuitry for thermoregulation, the balance between excitatory and inhibitory inputs to the dorsomedial hypothalamus (DMH) determines the level of activation of brown adipose tissue (BAT) thermogenesis. We employed neuroanatomical and in vivo electrophysiological techniques to identify a source of excitation to thermogenesis-promoting neurons in the DMH that is required for cold defense and fever. Inhibition of median preoptic area (MnPO) neurons blocked the BAT thermogenic responses during both PGE2-induced fever and cold exposure. Disinhibition or direct activation of MnPO neurons induced a BAT thermogenic response in warm rats. Blockade of ionotropic glutamate receptors in the DMH, or brain transection rostral to DMH, blocked cold-evoked or NMDA in MnPO-evoked BAT thermogenesis. RNAscope technique identified a glutamatergic population of MnPO neurons that projects to the DMH and expresses c-Fos following cold exposure. These discoveries relative to the glutamatergic drive to BAT sympathoexcitatory neurons in DMH augment our understanding of the central thermoregulatory circuitry in non-torpid mammals. Our data will contribute to the development of novel therapeutic approaches to induce therapeutic hypothermia for treating drug-resistant fever, and for improving glucose and energy homeostasis.
High frequency oscillations in epileptic and non-epileptic human hippocampus during a cognitive task
Authors: Pail Martin , Cimbálník Jan , Roman Robert , Daniel Pavel , Shaw Daniel J. , Chrastina Jan , Brázdil Milan
Published: October 2020

Hippocampal high-frequency electrographic activity (HFOs) represents one of the major discoveries not only in epilepsy research but also in cognitive science over the past few decades. A fundamental challenge, however, has been the fact that physiological HFOs associated with normal brain function overlap in frequency with pathological HFOs. We investigated the impact of a cognitive task on HFOs with the aim of improving differentiation between epileptic and non-epileptic hippocampi in humans. Hippocampal activity was recorded with depth electrodes in 15 patients with focal epilepsy during a resting period and subsequently during a cognitive task. HFOs in ripple and fast ripple frequency ranges were evaluated in both conditions, and their rate, spectral entropy, relative amplitude and duration were compared in epileptic and non-epileptic hippocampi. The similarity of HFOs properties recorded at rest in epileptic and non-epileptic hippocampi suggests that they cannot be used alone to distinguish between hippocampi. However, both ripples and fast ripples were observed with higher rates, higher relative amplitudes and longer durations at rest as well as during a cognitive task in epileptic compared with non-epileptic hippocampi. Moreover, during a cognitive task, significant reductions of HFOs rates were found in epileptic hippocampi. These reductions were not observed in non-epileptic hippocampi. Our results indicate that although both hippocampi generate HFOs with similar features that probably reflect non-pathological phenomena, it is possible to differentiate between epileptic and non-epileptic hippocampi using a simple odd-ball task.
Escherichia coli foster bladder cancer cell line progression via epithelial mesenchymal transition, stemness and metabolic reprogramming
Authors: Abd-El-Raouf Romaila , Ouf Salama A. , Gabr Mahmoud M. , Zakaria Mahmoud M. , El-Yasergy Khaled F. , Ali-El-Dein Bedeir
Published: October 2020

Bacteria is recognized as opportunistic tumor inhabitant, giving rise to an environmental stress that may alter tumor microenvironment, which directs cancer behavior. In vitro infection of the T24 cell line with E. coli was performed to study the bacterial impact on bladder cancer cells. EMT markers were assessed using immunohistochemistry, western blot and RT-PCR. Stemness characteristics were monitored using RT-PCR. Furthermore, the metabolic reprograming was investigated by detection of ROS and metabolic markers. A significant (p ≤ 0.001) upregulation of vimentin as well as downregulation of CK19 transcription and protein levels was reported. A significant increase (p ≤ 0.001) in the expression level of stemness markers (CD44, NANOG, SOX2 and OCT4) was reported. ROS level was elevated, that led to a significant increase (p ≤ 0.001) in UCP2. This enhanced a significant increase (p ≤ 0.001) in PDK1 to significantly downregulate PDH (p ≤ 0.001) in order to block oxidative phosphorylation in favor of glycolysis. This resulted in a significant decrease (p ≤ 0.001) of AMPK, and a significant elevation (p ≤ 0.001) of MCT1 to export the produced lactate to extracellular matrix. Thus, bacteria may induce alteration to the heterogonous tumor cell population through EMT, CSCs and metabolic reprogramming, which may improve cancer cell ability to migrate and self-renew.
Increasing thermal stability and improving biodistribution of VEGFR2-binding affibody molecules by a combination of in silico and directed evolution approaches
Authors: Güler Rezan , Svedmark Siri Flemming , Abouzayed Ayman , Orlova Anna , Löfblom John
Published: October 2020

The family of vascular endothelial growth factor (VEGF) ligands and their interactions with VEGF receptors (VEGFRs) play important roles in both pathological and physiological angiogenesis. Hence, agonistic and antagonistic ligands targeting this signaling pathway have potential for both studies on fundamental biology and for development of therapies and diagnostics. Here, we engineer VEGFR2-binding affibody molecules for increased thermostability, refolding and improved biodistribution. We designed libraries based on the original monomeric binders with the intention of reducing hydrophobicity, while retaining high affinity for VEGFR2. Libraries were displayed on bacteria and binders were isolated by fluorescence-activated cell sorting (FACS). In parallel, we used an automated sequence- and structure-based in silico algorithm to identify potentially stabilizing mutations. Monomeric variants isolated from the screening and the in silico approach, respectively, were characterized by circular dichroism spectroscopy and biosensor assays. The most promising mutations were combined into new monomeric constructs which were finally fused into a dimeric construct, resulting in a 15 °C increase in melting temperature, complete refolding capability after heat-induced denaturation, retained low picomolar affinity and improved biodistribution profile in an in vivo mouse model. These VEGFR2-binding affibody molecules show promise as candidates for further in vivo studies to assess their suitability as molecular imaging and therapeutic agents.
Anti-staphylococcal activity and mode of action of thioridazine photoproducts
Authors: Tozar Tatiana , Santos Costa Sofia , Udrea Ana-Maria , Nastasa Viorel , Couto Isabel , Viveiros Miguel , Pascu Mihail Lucian , Romanitan Mihaela Oana
Published: October 2020

Antibiotic resistance became an increasing risk for population health threatening our ability to fight infectious diseases. The objective of this study was to evaluate the activity of laser irradiated thioridazine (TZ) against clinically-relevant bacteria in view to fight antibiotic resistance. TZ in ultrapure water solutions was irradiated (1–240 min) with 266 nm pulsed laser radiation. Irradiated solutions were characterized by UV–Vis and FTIR absorption spectroscopy, thin layer chromatography, laser-induced fluorescence, and dynamic surface tension measurements. Molecular docking studies were made to evaluate the molecular mechanisms of photoproducts action against Staphylococcus aureus and MRSA. More general, solutions were evaluated for their antimicrobial and efflux inhibitory activity against a panel of bacteria of clinical relevance. We observed an enhanced antimicrobial activity of TZ photoproducts against Gram-positive bacteria. This was higher than ciprofloxacin effects for methicillin- and ciprofloxacin-resistant Staphylococcus aureus. Molecular docking showed the Penicillin-binding proteins PBP3 and PBP2a inhibition by sulforidazine as a possible mechanism of action against Staphylococcus aureus and MRSA strains, respectively. Irradiated TZ reveals possible advantages in the treatment of infectious diseases produced by antibiotic-resistant Gram-positive bacteria. TZ repurposing and its photoproducts, obtained by laser irradiation, show accelerated and low-costs of development if compared to chemical synthesis.
Atmospheric reaction of methyl mercaptan with hydroxyl radical as an acid rain primary agent
Authors: Douroudgari Hamed , Vahedpour Morteza , Mohammadi Samane
Published: October 2020

For the CH3SH + OH atmospheric reaction, we study the mechanism, potential energy surface, thermodynamic parameters of all stationary points, and rate of generation of the main product channels at high, low, and intermediate pressures. In this study, the UMP2, UM062X, UB3LYP, and CCSD(T) methods by Dunning and Pople basis sets are used and the results are compared with the experimental data. It is theoretically predicted that the reaction has fourteen possible pathways with eight different products in the gas phase. The thermodynamic results show that OH radical extracts predominantly the hydrogen of the SH functional group compared to the hydrogen of the CH3 group of CH3SH. Also, the rate constant calculations indicate that the extraction of the hydrogen atom of the SH group has a major role in 150–3000 K, while a good contribution is observed for the hydrogen of methyl group above 1200 K. Our results show that the used methods lead to good agreement with experiment. Finally, we demonstrated that why the main path is the main path.
Reptile species richness associated to ecological and historical variables in Iran
Authors: Kafash Anooshe , Ashrafi Sohrab , Yousefi Masoud , Rastegar-Pouyani Eskandar , Rajabizadeh Mahdi , Ahmadzadeh Faraham , Grünig Marc , Pellissier Loïc
Published: October 2020

Spatial gradients of species richness can be shaped by the interplay between historical and ecological factors. They might interact in particularly complex ways in heterogeneous mountainous landscapes with strong climatic and geological contrasts. We mapped the distribution of 171 lizard species to investigate species richness patterns for all species (171), diurnal species (101), and nocturnal species (70) separately. We related species richness with the historical (past climate change, mountain uplifting) and ecological variables (climate, topography and vegetation). We found that assemblages in the Western Zagros Mountains, north eastern and north western parts of Central Iranian Plateau have the highest number of lizard species. Among the investigated variables, annual mean temperature explained the largest variance for all species (10%) and nocturnal species (31%). For diurnal species, temperature change velocity shows strongest explained variance in observed richness pattern (26%). Together, our results reveal that areas with annual temperature of 15–20 °C, which receive 400–600 mm precipitation and experienced moderate level of climate change since the Last Glacial Maximum (LGM) have highest number of species. Documented patterns of our study provide a baseline for understanding the potential effect of ongoing climate change on lizard diversity in Iran.
Charge disproportionation and nano phase separation in $$\textit{R}\mathrm{SrNiO}_{4}$$
Authors: Guo H. , Li Z. W. , Chang C. F. , Hu Z. , Kuo C.-Y. , Perring T. G. , Schmidt W. , Piovano A. , Schmalzl K. , Walker H. C. , Lin H. J. , Chen C. T. , Blanco-Canosa S. , Schlappa J. , Schüßler-Langeheine C. , Hansmann P. , Khomskii D. I. , Tjeng L. H. , Komarek A. C.
Published: October 2020

We have successfully grown centimeter-sized layered $$\textit{R}\mathrm{SrNiO}_{4}$$

R

SrNiO
4

single crystals under high oxygen pressures of 120–150 bar by the floating zone technique. This enabled us to perform neutron scattering experiments where we observe close to quarter-integer magnetic peaks below $$\sim 77~\mathrm{K}$$

∼
77

K

that are accompanied by steep upwards dispersing spin excitations. Within the high-frequency Ni–O bond stretching phonon dispersion, a softening at the propagation vector for a checkerboard modulation can be observed. We were able to simulate the magnetic excitation spectra using a model that includes two essential ingredients, namely checkerboard charge disproportionation and nano phase separation. The results thus suggest that charge disproportionation is preferred instead of a Jahn–Teller distortion even for this layered $$\mathrm{Ni}^{3+}$$

Ni

3
+

system.
The fast-acting “pulse” of Heinrich Stadial 3 in a mid-latitude boreal ecosystem
Authors: Badino Federica , Pini Roberta , Bertuletti Paolo , Ravazzi Cesare , Delmonte Barbara , Monegato Giovanni , Reimer Paula , Vallé Francesca , Arrighi Simona , Bortolini Eugenio , Figus Carla , Lugli Federico , Maggi Valter , Marciani Giulia , Margaritora Davide , Oxilia Gregorio , Romandini Matteo , Silvestrini Sara , Benazzi Stefano
Published: October 2020

A 3800 year-long radiocarbon-dated and highly-resolved palaeoecological record from Lake Fimon (N-Italy) served to investigate the effects of potential teleconnections between North Atlantic and mid-to-low latitudes at the transition from Marine Isotope Stage (MIS) 3 to 2. Boreal ecosystems documented in the Fimon record reacted in a sensitive way to millennial and sub-millennial scale Northern Hemisphere atmospheric circulation patterns. The high median time-resolution of 58 years allows the identification of five abrupt event-boundaries (i.e., main forest expansion and decline excursions) synchronous with the sharp stadial/interstadial (GS/GI) transitions within dating uncertainties. During Heinrich Stadial 3 (HS 3) we reconstruct more open and dry conditions, compared to the other GS, with a dominant regional scale fire signal. Linkages between local fires and climate-driven fuel changes resulted in high-magnitude fire peaks close to GI/GS boundaries, even exacerbated by local peatland conditions. Finally, palaeoecological data from the HS 3 interval unveiled an internal variability suggesting a peak between 30,425 and 29,772 cal BP (2σ error) which matches more depleted δ18O values in alpine speleothems. We hypothesise that this signal, broadly resembling that of other mid-latitudes proxies, may be attributed to the southward shift of the Northern Hemisphere storm tracks and the associated delayed iceberg discharge events as documented during other HS.
Moving in unison after perceptual interruption
Authors: Bardy Benoît G. , Calabrese Carmela , De Lellis Pietro , Bourgeaud Stella , Colomer Clémentine , Pla Simon , di Bernardo Mario
Published: October 2020

Humans interact in groups through various perception and action channels. The continuity of interaction despite a transient loss of perceptual contact often exists and contributes to goal achievement. Here, we study the dynamics of this continuity, in two experiments involving groups of participants ($$N=7$$

N
=
7

) synchronizing their movements in space and in time. We show that behavioural unison can be maintained after perceptual contact has been lost, for about 7s. Agent similarity and spatial configuration in the group modulated synchronization performance, differently so when perceptual interaction was present or when it was memorized. Modelling these data through a network of oscillators enabled us to clarify the double origin of this memory effect, of individual and social nature. These results shed new light into why humans continue to move in unison after perceptual interruption, and are consequential for a wide variety of applications at work, in art and in sport.
A numerical study of pre-polarisation switching in ultra-low field magnetic resonance imaging using dynamic permanent magnet arrays
Authors: Pellicer-Guridi Ruben , Vogel Michael W. , Vegh Viktor , Su Jiasheng , Rosen Matthew S. , Reutens David C.
Published: October 2020

Dynamically adjustable permanent magnet arrays have been proposed to generate switchable magnetic fields for pre-polarisation in Ultra-Low Field magnetic resonance imaging. However, the optimal switching dynamics of the pre-polarisation magnetic field as well as the energy requirements, mechanical forces and stresses during switching of the pre-polarisation field have not been evaluated. We analysed these requirements numerically and estimated the magnetic resonance signal strength and image quality for two practical switching modes in an instrument suitable for scanning the human head. Von Mises stress analysis showed that although magnetic forces were significantly higher for two specific rungs, the structural integrity of magnet rungs would not be compromised. Our simulations suggest that a significantly higher signal yield is obtained by switching off the pre-polarisation field with the angular velocity in each rung dependent on its location.
Author Correction: Potent effects of dioscin against obesity in mice
Authors: Liu Min , Xu Lina , Yin Lianhong , Qi Yan , Xu Youwei , Han Xu , Zhao Yanyan , Sun Huijun , Yao Jihong , Lin Yuan , Liu Kexin , Peng Jinyong
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.