bluuebunny/crossref_metadata_2025 huggingface dataset:
Australia's earliest tetrapod swimming traces from the Hawkesbury Sandstone (Middle Triassic) of the Sydney Basin
Authors: Farman Roy M. , Bell Phil R.
Published: May 2020

The Hawkesbury Sandstone (Hawkesbury Series, Sydney Basin) on the southeastern coast of New South Wales, Australia, preserves a depauperate but important vertebrate tetrapod body-fossil record from the Early and Middle Triassic. As with many fossil sites around the world, the ichnological record has helped to shed light on the paleoecology of this interval. Herein, we investigate historical reports of a trackway pertaining to a putative short-tailed reptile found at Berowra Creek in the 1940s. Reinvestigation of the surviving track-bearing slabs augmented by archival photographs of the complete trackway, suggests that these impressions, which consist primarily of didactyl tracks (plus less common monodactyl and tridactyl traces), represent the earliest example of a swimming tetrapod found in Australia. Another isolated specimen (possibly from a nearby locality at Annangrove) appears to represent similar didactyl swim traces of a second, larger individual. Although the identities of the trackmakers are unknown, the Berowra Creek individual had an estimated body length of between ~80 cm (short-coupled) and 1.35 m (long-coupled), and produced the subaqueous trackway while travelling upslope (against the current) on a sandbar within a braided river system of the Hawkesbury Sandstone. These trackways partially resemble amphibian swim traces in the so-called Batrachichnus C Lunichnium continuum, but appear to represent a unique locomotion trace. This reanalysis of the Berowra Creek trackway provides insight into the locomotion of tetrapods of the Triassic Hawkesbury Series, which remains a poorly understood aspect of their life history.
Exploring test batteries for depression- and anxiety-like behaviours in female and male ICR and black Swiss mice
Authors: Kazavchinsky Lydmila , Dahan Sofi , Einat Haim
Published: May 2020

Objective and rationale: Animal models are critical for the study of mental disorders and their treatments but are repeatedly criticized for problems with validity and reproducibility. One approach to enhance validity and reproducibility of models is to use test batteries rather than single tests. Yet, a question regarding batteries is whether one can expect a consistent individual behavioural phenotype in mice across tests that can be presumed to be part of the same construct. This study was designed to explore the relationship between the behaviours of mice across tests in some variations of test batteries for depression- and anxiety-like behaviours. Methods: Female and male healthy, intact, and untreated mice from the ICR and black Swiss strains were used in four separate experiments. With some variations, mice were exposed to a battery of behavioural tests representing affective- and anxiety-like behaviours. Data were analysed for differences between sexes and for correlations between behaviours within and across the tests in the battery. Results: No differences were found between the sexes. With very few exceptions, we found correlations within tests (when one test has more than one measure or is repeated) but not across different tests within the battery. Conclusions: The results cast some doubt on the utility of behavioural test batteries to represent different facets of emotional behaviour in healthy intact outbred mice, without any interventions or treatments. Additional studies are designed to explore whether stronger relationship between the tests will appear after manipulations or drug treatments.
THE GATE COMPLEX OF PLANCIA MAGNA IN PERGE: A CASE STUDY IN READING BILINGUAL SPACE
Authors: Gatzke Andrea F.
Published: May 2020

Urban landscapes in the Roman world were covered in written text, from monumental building inscriptions to smaller, more personal texts of individual accomplishment and commemoration. In the East, Greek dominated these written landscapes, but Latin also appeared with some frequency, especially in places where a larger Roman audience was expected, such as major cities and Roman colonies. When Latin and Greek appear alongside each other, whether in the same inscription or across a single monumental space, we might ask what benefits the sponsor of the monument hoped to gain from such a bilingual presentation, and whether each language was serving the same function. This paper considers the monumental entrance to the Pamphylian city of Perge as a case study for exploring this relationship between bilingual inscriptions and civic space. By surveying the display of both Greek and Latin on this entrance, examining how the entrance interacted with the broader linguistic landscape of Perge, and considering the effects that each language would have had on the viewer, I show that the use of language, and the variation between the languages, served not only to communicate membership in both Greek and Roman societies but also to delineate civic space from imperial space, both physically and symbolically.
NONBINARY DELSARTE–GOETHALS CODES AND FINITE SEMIFIELDS
Authors: RÚA IGNACIO F.
Published: May 2020

Symplectic finite semifields can be used to construct nonlinear binary codes of Kerdock type (i.e., with the same parameters of the Kerdock codes, a subclass of Delsarte–Goethals codes). In this paper, we introduce nonbinary Delsarte–Goethals codes of parameters
$(q^{m+1}\ ,\ q^{m(r+2)+2}\ ,\ {\frac{q-1}{q}(q^{m+1}-q^{\frac{m+1}{2}+r})})$
over a Galois field of order
$q=2^l$
, for all
$0\le r\le\frac{m-1}{2}$
, with m ≥ 3 odd, and show the connection of this construction to finite semifields.
Selection of nonlinear mixed models for growth curves of dairy buffaloes (Bubalus bubalis)
Authors: Araujo Neto F. R. , Oliveira D. P. , Aspilcueta-Borquis R. R. , Vieira D. A. , Guimarães K. C. , Oliveira H. N. , Tonhati H.
Published: May 2020

The determination of livestock growth patterns is important for meat or milk production systems, and nonlinear models are used to summarize and interpret the information. The aim of this study was to more accurately estimate growth curve parameters in buffalo cows by evaluating and selecting nonlinear mixed models that employ different types of residuals and include or not contemporary groups (CG) as a covariate. Weight records from 720 animals obtained over a period of 60 months were used. The growth curves were fit using nonlinear mixed-effects models. The Bertalanffy, Gompertz and Logistic models were evaluated. Modelling residuals using four structures (constant, combined, exponential and proportional) and the inclusion or not of CG in the models were also evaluated. The Akaike information criterion (AIC) and Bayesian information criterion (BIC) were used to select the model. In addition to estimating the parameters of the nonlinear growth models and their correlations, the instantaneous growth rate and inflection point were obtained. The Bertalanffy model with a combined residual structure and CG exhibited the lowest AIC and BIC values. Asymptotic weight (A) estimates ranged from 621.8 to 742.1 kg, and the maturity rate (k) ranged from 0.068 to 0.115 kg/month. The correlation between A and k ranged from −0.32 to −0.82 among the models evaluated. The selection criteria indicated that the Bertalanffy model was the most suitable for growth curve analysis in buffaloes.
State Preventive Medicine: Public Health, Indian Removal, and the Growth of State Capacity, 1800–1840
Authors: Bloch Rubin Ruth
Published: May 2020

Despite growing awareness of the American state's active role in the early nineteenth century, scholars have tended to ignore the early republic's public health apparatus. The few studies that do chronicle antebellum health initiatives confine themselves to programs intended to directly reward citizens—and particularly those who contributed politically or economically to the nation's founding and expansion. As this detailed study of the Indian Vaccination Act of 1832 makes clear, however, antebellum policymakers saw value in providing medical care to those outside their settler citizenry. Blending liberal, republican, and ascriptive ideas, the vaccination program joined two competing political logics: one emphasizing the humanity of indigenous people and the importance of providing for their welfare, and the other prioritizing the state's interest in an efficient “removal” process. Evidencing far more autonomy and administrative capacity than the average nineteenth-century bureaucracy, the War Department played a pivotal role in petitioning Congress for, and ultimately administering, the vaccination program. Unwilling to cede regulatory power over indigenous health to more proximate local governments or private parties, the War Department preferred its own military manpower—a decision that would profoundly shape the design and reception of subsequent Native health programs.
Type and Token in the Prehistoric Origins of Numbers
Authors: Schlaudt Oliver
Published: May 2020

The type–token distinction and the notion of ‘tokenization’ are proposed as analytical tools that may help us understand better the emergence of numbers and mathematical thinking from the non-mathematical cultural practices of the Upper Palaeolithic such as painting, decorating portable objects, or making ornaments from beads, as described in recent studies in cognitive archaeology. While the type–token distinction has been a salient element in recent debates in the philosophy of mathematics, it seems not yet to have been registered in those areas of cognitive archaeology concerned with numbers—and yet it may help to identify the circumstances under which the conceptual potential of cultural artefacts develops. The concept of tokenization permits us to identify a plausible link between non-numerical cultural resources and the emergence of numerical thought patterns. This approach offers a way of appreciating the role of artefacts without raising the notoriously difficult question of their original ‘meaning’.
Next year, if grain is dear, I shall be a Sayyid: Sayyid Ahmad Khan, colonial constructions, and Muslim self-definitions
Authors: LELYVELD DAVID
Published: May 2020

British social surveys and census statistics defined ‘Sayyid’ as a caste identity, while often casting a sceptical eye on the authenticity of genealogical claims associated with the concept. The article examines how Muslims, especially Sayyid Ahmad Khan, participated in the formulation of the concept of Sayyid identity and status. Islamic ideology and practice have long wrestled with conflicting claims of religious equality and hierarchical status, often based on concepts of sacred lineage. From his earliest writings Sayyid Ahmad Khan (1817–98) emphasised his descent from the Prophet Muhammad on his father's side alongside his somewhat less exalted relationship with his Kashmiri grandfather. In later years he tried to balance universalistic ideals with claims to status based on supposedly ‘foreign’ ancestry, which he cited as parallel to the supposed Aryan ancestry of high-status Hindus. His British allies used his Sayyid ancestry as reinforcement of his leadership of an India-wide Muslim ‘community’ and evidence that India was not prepared to develop into a national polity based on representative government. But the Aligarh movement's claim to represent the wider Muslim population and in particular its educational project at Aligarh struggled with a more egalitarian ethos, defining students and the members of voluntary associations as ‘brothers’, and quite prepared to cross ascriptive boundaries both in public life and personal relationships.
Contract work at older ages
Authors: Abraham Katharine G. , Hershbein Brad , Houseman Susan N.
Published: May 2020

The share of workers who are self-employed rises markedly with age. Given policy concerns about inadequate retirement savings, especially among those with lower education, and the resulting interest in encouraging employment at older ages, it is important to understand the role that self-employment arrangements play in facilitating work among seniors. New data from a survey module fielded on a Gallup telephone survey distinguish independent contractor work from other self-employment and provide information on informal and online platform work. The Gallup data show that, especially after accounting for individuals who are miscoded as employees, self-employment is even more prevalent at older ages than suggested by existing data. Work as an independent contractor is the most common type of self-employment. Roughly one-quarter of independent contractors aged 50 and older work for a former employer. At older ages, self-employment generally – and work as an independent contractor specifically – is more common among the highly educated, accounting for much of the difference in employment rates across education groups. We provide suggestive evidence that differences in opportunities for independent contractor work play an important role in the lower employment rates of less-educated older adults.
SYMBOLIC ANALYTIC SPREAD: UPPER BOUNDS AND APPLICATIONS
Authors: Dao Hailong , Montaño Jonathan
Published: May 2020

The symbolic analytic spread of an ideal $I$ is defined in terms of the rate of growth of the minimal number of generators of its symbolic powers. In this article, we find upper bounds for the symbolic analytic spread under certain conditions in terms of other invariants of $I$. Our methods also work for more general systems of ideals. As applications, we provide bounds for the (local) Kodaira dimension of divisors, the arithmetic rank, and the Frobenius complexity. We also show sufficient conditions for an ideal to be a set-theoretic complete intersection.
Pesticide regulation in the European Union and the glyphosate controversy
Authors: Kudsk Per , Mathiassen Solvejg Kopp
Published: May 2020

The glyphosate controversy before the renewal of the authorization of glyphosate in the European Union (EU) once again turned the spotlight on pesticide regulation in the EU. In the EU, pesticides are attracting more public attention than in other parts of the world, and many nongovernmental organizations specifically target pesticide regulation, trying to influence politicians and other decision makers. Following an overview of the EU pesticide legislation and the impact hitherto on EU agriculture, this paper outlines the glyphosate controversy and presents the outcome of desk studies conducted in Germany, the United Kingdom, France, and Sweden on the potential effects of a glyphosate ban on agricultural productivity and farm income. All studies concluded that the loss of income depends very much on farm type and cropping practice, but they all reached the conclusion that particularly no-tillage farming/conservation agriculture will be facing severe problems without glyphosate to control weeds and terminate cover crops. No-tillage/conservation agriculture is viewed as an effective strategy to prevent soil erosion and loss of nutrients, which could become larger problems without glyphosate. Other issues highlighted in the studies were the impact on resistance management, as glyphosate is largely seen as a “herbicide-resistance breaker.” Without glyphosate, fundamental changes in farming practices in the EU are required, and it is hard to imagine that they will come without a cost, at least in the short term.
Tribulus Terrestrismay decrease muscle damage markers following a high-intensity resistance exercise: A pilot study
Authors: Talemi Mohammad Nasir Pour Eshmanan , Ardakani Seyed Mojtaba Paydar , Roozbeh Behnam
Published: May 2020

Abstract. The purpose of this study was to investigate the effect of two weeks of Tribulus Terrestris ( TT) on the responses of Interleukin-6 (IL-6), high sensitivity C-reactive protein (hs-CRP), and enzymes creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) following a single session of resistance exercise (RE). Eighteen healthy non-athlete males (age: 22.44 ± 2.54 years, BMI: 26.15 ± 1.62 kg/m2) participated in this study and were divided randomly into two 9-person groups of supplementation or placebo. The participants consumed two 250-mg capsules of TT or placebo (maltodextrin) per day and performed six REs with the intensity 80, 85, and 90% of 1RM in three circles at the day after the end of supplementation period. Blood samples were collected before the initiation of supplementation, and before and after the RE session. Total changes of IL-6 ( p<0.001) and LDH ( p=0.005) were significant in both groups. Bonferroni post hoc test showed that increased values of IL-6 and CPK in both groups were significant after exercise compared with pre-exercise and baseline ( p<0.001). There were no significant differences in relation to within- and between-group changes in hs-CRP ( p>0.05). Moreover, differences between the groups regarding post-exercise IL-6 and CPK were not significant ( p>0.05). However, post-exercise LDH in supplementation group were lower than placebo group ( p=0.015). In conclusion, short-term supplementation with TT has no effect on IL-6 and hs-CRP, but may be effective on the reduction of muscle damage enzymes CPK and LDH following high-intensity circuit RE.
Error Processing During the Online Retrieval of Probabilistic Sequence Knowledge
Authors: Horváth Kata , Kardos Zsófia , Takács Ádám , Csépe Valéria , Nemeth Dezso , Janacsek Karolina , Kóbor Andrea
Published: May 2020

Abstract. Adaptive behavior involves rapid error processing and action evaluation. However, it has not been clarified how errors contribute to automatic behaviors that can be retrieved to successfully adapt to our complex environment. Automatic behaviors strongly rely on the process of probabilistic sequence learning and memory. Therefore, the present study investigated error processing during the online retrieval of probabilistic sequence knowledge. Twenty-four healthy young adults acquired and continuously retrieved a repeating stimulus sequence reflected by reaction time (RT) changes on a rapid forced-choice RT task. Performance was compared with a baseline that denoted the processing of random stimuli embedded in the probabilistic sequence. At the neurophysiological level, event-related brain potentials synchronized to responses were measured. Error processing was tracked by the error negativity (Ne) and the error positivity (Pe). The mean amplitude of the Ne gradually decreased as the task progressed, similarly for the sequence retrieval and the embedded baseline process. The mean amplitude of the Pe increased over time, likewise, irrespective of the type of the stimuli. Accordingly, we propose that automatic error detection (Ne) and conscious error evaluation (Pe) are not sensitive to sequence learning and retrieval. Overall, the present study provides insight into how error processing takes place for the retrieval of sequence knowledge in a probabilistic environment.
Unraveling the Electrophysiological Activity Behind Recognition Memory
Authors: Andreau Jorge Mario , Idesis Sebastián Ariel , Iorio Alberto Andrés
Published: May 2020

Abstract. Traditionally, most event related potential (ERP) studies of memory retrieval have been reported during item-recognition tasks. Those studies lead to two well-known ERP memory components termed FN400 (familiarity) and LPC (recollection). Nevertheless, some critics have raised concerns regarding the actual meaning of that activity since it emerges as the result of contrasting two different memory traces (previously studied vs. seen for the first time), and it is registered after the target presentation. Therefore, they possibly depict operations not related to memory itself but some cognitive processes associated with recognition memory. Based on those critics, we propose an innovative approach to study electrophysiological activity underlying recognition memory. We compared two very similar tasks with only one of them requiring subjects to actively retrieve a “cue-target” pair of visual stimuli from memory, while the other task required subjects to recognize the target stimulus as equal/different to the cue. Because of this experimental manipulation, we assured that active memory retrieval processes take place between the presentation of the cue and the target stimuli for only one of the tasks. As a result, responses upon the targets can give us valuable information regarding ERP components associated with recognition based on memory retrieval. We found three components possibly related to brain computations necessary to achieve correct target recognition. A N200-like component linked to executive functions (inhibition) from frontal cortices, a P300-like component, related to the expectation of the target stimulus, and a P600-like component associated to recognition based on LTM retrieval. These results help us to understand the complexity behind ERP components associated with recognition memory.
Oncogenic super-enhancer formation in tumorigenesis and its molecular mechanisms
Authors: Jia Qunying , Chen Shuhua , Tan Yuan , Li Yuejin , Tang Faqing
Published: May 2020

Super-enhancers (SEs) consist of a cluster of many enhancers bound to a great number of transcription factors. They are critical cis-regulatory elements that determine the identity of various human cell types. During tumorigenesis, DNA mutations and indels, chromosomal rearrangements, three-dimensional chromatin structural changes, and viral infections mediate oncogenic SE activation, and activated SEs have been found to regulate the expression of oncogenic genes. Inhibition specifically targeted to oncogenic SE assembly and activation provides a novel powerful therapeutic strategy for various cancers. In this paper, we first introduce the current understanding of oncogenic SE assembly and activation and then summarize the pathogenic factors and mechanism of oncogenic SE activation. Next, we elaborate on the oncogenic functions of SEs in cancers and the application of SEs as therapeutic targets. Finally, we turn our focus to the use of SEs in basic research and clinical trials.
TRIM11 facilitates chemoresistance in nasopharyngeal carcinoma by activating the β-catenin/ABCC9 axis via p62-selective autophagic degradation of Daple
Authors: Zhang Runa , Li Si-Wei , Liu Lijuan , Yang Jun , Huang Guofu , Sang Yi
Published: May 2020

Chemotherapy resistance is the major cause of nasopharyngeal carcinoma (NPC) treatment failure. Tripartite motif-containing protein (TRIM) family members play important roles in tumor development and chemotherapy failure. Here, based on a screening analysis of 71 TRIM family members by qRT-PCR, we first confirmed that the TRIM11 levels were significantly higher in drug-resistant NPC cells than in non-drug-resistant NPC cells, and high TRIM11 expression predicted poor overall survival (OS) and progression-free survival (PFS). N(6)-Methyladenosine (m6A) was highly enriched in TRIM11 in NPC drug-resistant cells and enhanced its RNA stability. TRIM11 enhanced the multidrug resistance in NPC by inhibiting apoptosis in vitro and promoting cisplatin (DDP) resistance in vivo. TRIM11 associated with Daple and promoted Daple ubiquitin-mediated degradation in a p62-selective autophagic manner, further upregulating β-catenin expression to induce ABCC9 expression by directly binding to the ABCC9 promoter. TRIM11 may regulate NPC drug resistance by positively modulating the Daple/β-catenin/ABCC9 signaling pathway. Thus, TRIM11 may be a potential diagnostic marker and therapeutic target for chemoresistant NPC.
Clinical utility of the exosome based ExoDx Prostate(IntelliScore) EPI test in men presenting for initial Biopsy with a PSA 2–10 ng/mL
Authors: Tutrone Ronald , Donovan Michael J. , Torkler Phillipp , Tadigotla Vasisht , McLain Tom , Noerholm Mikkel , Skog Johan , McKiernan James
Published: May 2020

Background

The ExoDx Prostate(IntelliScore) (EPI) test is a non-invasive risk assessment tool for detection of high-grade prostate cancer (HGPC) that informs whether to proceed with prostate biopsy. We sought to assess the impact of EPI on the decision to biopsy in a real-world clinical setting.

Methods

We conducted a prospective, randomized, blinded, two-armed clinical utility study that enrolled 1094 patients with 72 urologists from 24 urology practices. Patients were considered for prostate biopsy at enrollment based on standard clinical criteria. All patients had an EPI test; however, patients were randomized into EPI vs. control arms where only the EPI arm received results for their biopsy decision.

Results

In the EPI arm (N = 458), 93 patients received negative EPI scores of which 63% were recommended to defer biopsy by the urologist and 74% ultimately deferred. In contrast, 87% of patients with positive EPI scores were recommended to undergo biopsy with a 72% compliance rate to the urologist’s recommendation. This led to detection of 30% more HGPC compared to the control arm, and we estimate that 49% fewer HGPC were missed due to deferrals compared to standard of care (SOC). Overall, 68% of urologists reported that the EPI test influenced their biopsy decision. The primary reason not to comply with EPI results was rising PSA.

Conclusion

To our knowledge this is the first report on a PC biomarker utility study with a blinded control arm. The study demonstrates that the EPI test influences the overall decision to defer or proceed with a biopsy and improves patient stratification.
WTAP and BIRC3 are involved in the posttranscriptional mechanisms that impact on the expression and activity of the human lactonase PON2
Authors: Carusone Teresa Maria , Cardiero Giovanna , Cerreta Mariangela , Mandrich Luigi , Moran Oscar , Porzio Elena , Catara Giuliana , Lacerra Giuseppina , Manco Giuseppe
Published: May 2020

The activity of human paraoxonase 2 (PON2) is rapidly reduced in cells incubated with the bacterial quorormone 3-Oxo-dodecanoyl Homoserine Lactone (3OC12HSL), an observation that led to hypothesize a fast PON2 post-translational modification (PTM). Recently, we detected a 3OC12HSL-induced PTM in a cell-free system in which a crude extract from 3OC12HSL-treated HeLa cells was able to inactivate and ubiquitinate at position 144 a recombinant PON2. Here we show the occurrence of this and new PTMs on PON2 in HeLa cells. PTMs were found to gather nearby the two SNPs, A148G, and S311C, that are related to type-2 diabetes and its complications. Furthermore, we detected a PTM nearby a 12 amino acids region that is deleted in PON2 Isoform 2. An in vitro mutation analysis showed that the SNPs and the deletion are involved in PON2 activity and suggested a role of PTMs on its modulation, while a SAXS analysis pointed to Isoform 2 as being largely unstructured, compared to the wild type. Besides, we discovered a control of PON2 expression via a putative mRNA operon involving the Wilms tumor 1 associated protein (WTAP) and the E3 ubiquitin ligase (E3UbL) baculoviral IAP repeat-containing 3 (BIRC3).
Exosomes derived from hucMSC attenuate renal fibrosis through CK1δ/β-TRCP-mediated YAP degradation
Authors: Ji Cheng , Zhang Jiahui , Zhu Yuan , Shi Hui , Yin Siqi , Sun Fengtian , Wang Qiongni , Zhang Leilei , Yan Yongmin , Zhang Xu , Xu Wenrong , Qian Hui
Published: May 2020

Exosomes from human umbilical cord mesenchymal stem cells (hucMSC-Ex) have been suggested as novel nanomaterials for regenerative medicine. Here we explored the roles of hucMSC-Ex through regulating Yes-associated protein (YAP) in renal injury repair by using rat unilateral ureteral obstruction (UUO) models. Our study identified mechanical stress induced YAP nucleus expression and stimulated collagen deposition and interstitial fibrosis in the kidney. Then, infusion with hucMSC-Ex promoted YAP nuclear cytoplasmic shuttling and ameliorated renal fibrosis in UUO model. Interestingly, hucMSC-Ex delivered casein kinase 1δ (CK1δ) and E3 ubiquitin ligase β-TRCP to boost YAP ubiquitination and degradation. Knockdown of CK1δ and β-TRCP in hucMSC decreased the repairing effects of hucMSC-Ex on renal fibrosis. Our results suggest that hucMSC-Ex attenuates renal fibrosis through CK1δ/β-TRCP inhibited YAP activity, unveiling a new mechanism for the therapeutic effects of hucMSC-Ex on tissue injury and offering a potential approach for renal fibrosis treatment.
NF-kappa B interacting long noncoding RNA enhances the Warburg effect and angiogenesis and is associated with decreased survival of patients with gliomas
Authors: Chen Zheng , Li Shiting , Shen Lin , Wei Xiangyu , Zhu Hanshuo , Wang Xueyi , Yang Min , Zheng Xuesheng
Published: May 2020

Abstract

In various malignant tumors, NF-kappa B interacting long noncoding RNA (NKILA) displays antitumor activity by inhibiting the NF-kappa B pathway. However, the role of NKILA in gliomas remains unclear. Surprisingly, this study showed that NKILA is significantly upregulated in gliomas, and the increased levels of NKILA were correlated with a decrease in patient survival time. NKILA increased the expression level of hypoxia-inducible factor-1α, and the activity of the hypoxia pathway in gliomas. Furthermore, we demonstrated that NKILA enhances the Warburg effect and angiogenesis in gliomas both in vitro and in vivo. Therefore, NKILA is a potential therapeutic target in gliomas. In addition, we showed that a 20(S)-Rg3 monomer suppresses NKILA accumulation and reverses its stimulation of the Warburg effect and angiogenesis in gliomas, both in vitro and in vivo. Therefore, this study not only identified NKILA as a potential therapeutic target in gliomas, but also demonstrated a practical approach to treatment.
PKCθ-JunB axis via upregulation of VEGFR3 expression mediates hypoxia-induced pathological retinal neovascularization
Authors: Kumar Raj , Mani Arul M. , Singh Nikhlesh K. , Rao Gadiparthi N.
Published: May 2020

Pathological retinal neovascularization is the most common cause of vision loss. PKCθ has been shown to play a role in type 2 diabetes, which is linked to retinal neovascularization. Based on these clues, we have studied the role of PKCθ and its downstream target genes JunB and VEGFR3 in retinal neovascularization using global and tissue-specific knockout mouse models along with molecular biological approaches. Here, we show that vascular endothelial growth factor A (VEGFA) induces PKCθ phosphorylation in human retinal microvascular endothelial cells (HRMVECs) and downregulation of its levels attenuates VEGFA-induced HRMVECs migration, sprouting and tube formation. Furthermore, the whole body deletion of PKCθ or EC-specific deletion of its target gene JunB inhibited hypoxia-induced retinal EC proliferation, tip cell formation and neovascularization. VEGFA also induced VEGFR3 expression via JunB downstream to PKCθ in the regulation of HRMVEC migration, sprouting, and tube formation in vitro and OIR-induced retinal EC proliferation, tip cell formation and neovascularization in vivo. In addition, VEGFA-induced VEGFR3 expression requires VEGFR2 activation upstream to PKCθ-JunB axis both in vitro and in vivo. Depletion of VEGFR2 or VEGFR3 levels attenuated VEGFA-induced HRMVEC migration, sprouting and tube formation in vitro and retinal neovascularization in vivo and it appears that these events were dependent on STAT3 activation. Furthermore, the observations using soluble VEGFR3 indicate that VEGFR3 mediates its effects on retinal neovascularization in a ligand dependent and independent manner downstream to VEGFR2. Together, these observations suggest that PKCθ-dependent JunB-mediated VEGFR3 expression targeting STAT3 activation is required for VEGFA/VEGFR2-induced retinal neovascularization.
QKI deficiency leads to osteoporosis by promoting RANKL-induced osteoclastogenesis and disrupting bone metabolism
Authors: Du Tianshu , Yan Zhao , Zhu Shu , Chen Guo , Wang Li , Ye Zichen , Wang Wenwen , Zhu Qingsheng , Lu Zifan , Cao Xiaorui
Published: May 2020

Quaking (QKI), an RNA-binding protein, has been reported to exhibit numerous biological functions, such as mRNA regulation, cancer suppression, and anti-inflammation. However, little known about the effects of QKI on bone metabolism. In this study, we used a monocyte/macrophage-specific QKI knockout transgenic mouse model to investigate the effects of QKI deficiency on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. The loss of QKI promoted the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts (OCs) from bone marrow macrophages, and upregulated the expression of OC-specific markers, including TRAP (Acp5) and cathepsin K (Ctsk). The pro-osteoclastogenesis effect of QKI deficiency was achieved by amplifying the signaling cascades of the NF-κB and mitogen-activated protein kinase (MAPK) pathways; then, signaling upregulated the activation of nuclear factor of activated T cells c1 (NFATc1), which is considered to be the core transcription factor that regulates OC differentiation. In addition, QKI deficiency could inhibit osteoblast (OB) formation through the inflammatory microenvironment. Taken together, our data suggest that QKI deficiency promoted OC differentiation and disrupted bone metabolic balance, and eventually led to osteopenia under physiological conditions and aggravated the degree of osteoporosis under pathological conditions.
NT5DC2 promotes tumor cell proliferation by stabilizing EGFR in hepatocellular carcinoma
Authors: Li Kang-Shuai , Zhu Xiao-Dong , Liu Hong-Da , Zhang Shi-Zhe , Li Xiao-Long , Xiao Nan , Liu Xue-Feng , Xu Bin , Lei Ming , Zhang Yuan-Yuan , Shi Wen-Kai , Cao Man-Qing , Xu Yun-Fei , Tang Zhao-You , Sun Hui-Chuan
Published: May 2020

Most hepatocellular carcinoma (HCC) patients are diagnosed at an advanced stage; however, the effect of systemic therapy on advanced HCC remains undetermined. Therefore, new treatment targets must be identified. We analyzed Gene Expression Omnibus datasets from two HCC patient cohorts and found that NT5DC2 was associated with vascular invasion and poor survival. In two hepatoma cell lines, NT5DC2 overexpression promoted HCC cell proliferation and clone formation in vitro and promoted tumor growth in vivo. Coimmunoprecipitation assays and liquid chromatography with tandem mass spectrometry analysis revealed that NT5DC2 bound directly to epidermal growth factor receptor (EGFR). NT5DC2 upregulated EGFR expression by downregulating EGFR ubiquitination and preventing its degradation via the ubiquitin-proteasome pathway but did not upregulate its transcription. EGFR upregulation activated downstream signal transduction, which played a critical role in the protumor effects of NT5DC2. Erlotinib, a small-molecule inhibitor of EGFR, blocked the effect of NT5DC2 in promoting HCC cell proliferation. In a cohort of 79 patients who underwent curative resection for HCC, NT5DC2 expression in the tumors was associated with larger tumors and microvascular invasion. NT5DC2 expression was also independently associated with recurrence-free survival. The present study demonstrated for the first time that NT5DC2 promotes tumor cell proliferation in HCC and may serve as a potential molecular target for treating HCC. EGFR blockage could be used to treat selected patients with NT5DC2 upregulation.
LncRNA SNORD3A specifically sensitizes breast cancer cells to 5-FU by sponging miR-185-5p to enhance UMPS expression
Authors: Luo Liyun , Zhang Jianlei , Tang Hailin , Zhai Dongfeng , Huang Danqing , Ling Li , Wang Xiaorong , Liu Ting , Zhang Qiong , Zhang Zhijie , He Zhimin , Zheng Guopei
Published: May 2020

Breast cancer is the most common cancer type in women. Long non-coding RNAs (lncRNAs) have been reported as potential new diagnostic markers, prognostic factors, and therapeutic targets in cancer. However, the specific roles and mechanisms of lncRNAs in breast cancer remain to be elucidated. Here we demonstrated the downregulation of lncRNA SNORD3A in breast cancer cells and tissues and verified its non-protein-coding property. SNORD3A overexpression had no effect on cell proliferation but specifically sensitized breast cancer cells to 5-fluorouracil (5-FU) in vitro and in vivo. Mechanistically, SNORD3A exerts its effect via enhancing uridine monophosphate synthetase (UMPS) protein expression. SNORD3A acts as a competing endogenous RNA for miR-185-5p, leading to UMPS protein upregulation. miR-185-5p overexpression disrupted the effect of SNORD3A on chemosensitization to 5-FU in vitro and in vivo. Moreover, Meis1 overexpression transcriptionally promotes SNORD3A expression, and Meis1 is downregulated in breast cancer cells and tissues. In breast cancer tissues, SNORD3A level positively correlates with Meis1 and UMPS protein levels, whereas miR-185-5p level negatively correlates with UMPS protein level. High SNORD3A transcript and Meis1 and UMPS protein levels predicts a better outcome, but high miR-185-5p level predicts a worse outcome in breast cancer patients receiving 5-FU-based chemotherapy. Our findings indicate that Meis1-regulated SNORD3A specifically sensitizes breast cancer cells to 5-FU via enhancing UMPS expression. The SNORD3A–UMPS axis may serve as a potential biomarker and therapeutic target to improve the efficacy of 5-FU-based chemotherapy for breast cancer patients.
On-demand tuning of charge accumulation and carrier mobility in quantum dot solids for electron transport and energy storage devices
Authors: Septianto Ricky Dwi , Liu Liming , Iskandar Ferry , Matsushita Nobuhiro , Iwasa Yoshihiro , Bisri Satria Zulkarnaen
Published: May 2020

Assemblies of colloidal quantum dots (CQDs) are attractive for a broad range of applications because of the ability to exploit the quantum confinement effect and the large surface-to-volume ratio due to their small dimensions. Each application requires different types of assemblies based on which properties are intended to be utilized. Greater control of assembly formation and optimization of the related carrier transport characteristics are vital to advance the utilization of these materials. Here, we demonstrate on-demand control of the assembly morphology and electrical properties of highly crosslinked CQD solids through the augmentation of various assembly methods. Employment of electric-double-layer (EDL) gating on these assembly structures (i.e., an amorphous assembly, a hierarchical porous assembly, and a compact superlattice assembly) reveals their intrinsic carrier transport and accumulation characteristics. Demonstrations of high electron mobility with a high current modulation ratio reaching 105 in compact QD films and of a record-high areal capacitance of 400 μF/cm2 in an electric-double-layer supercapacitor with very thin (<100 nm) QD hierarchical porous assemblies signify the versatility of CQDs as building blocks for various modern electronic devices.
Early Jurassic dinosaur fetal dental development and its significance for the evolution of sauropod dentition
Authors: Reisz Robert R. , LeBlanc Aaron R. H. , Maddin Hillary C. , Dudgeon Thomas W. , Scott Diane , Huang Timothy , Chen Jun , Chen Chuan-Mu , Zhong Shiming
Published: May 2020

Rare occurrences of dinosaurian embryos are punctuated by even rarer preservation of their development. Here we report on dental development in multiple embryos of the Early Jurassic Lufengosaurus from China, and compare these to patterns in a hatchling and adults. Histology and CT data show that dental formation and development occurred early in ontogeny, with several cycles of tooth development without root resorption occurring within a common crypt prior to hatching. This differs from the condition in hatchling and adult teeth of Lufengosaurus, and is reminiscent of the complex dentitions of some adult sauropods, suggesting that their derived dental systems likely evolved through paedomorphosis. Ontogenetic changes in successive generations of embryonic teeth of Lufengosaurus suggest that the pencil-like teeth in many sauropods also evolved via paedomorphosis, providing a mechanism for the convergent evolution of small, structurally simple teeth in giant diplodocoids and titanosaurids. Therefore, such developmental perturbations, more commonly associated with small vertebrates, were likely also essential events in sauropod evolution.
Damped circadian oscillation in the absence of KaiA in Synechococcus
Authors: Kawamoto Naohiro , Ito Hiroshi , Tokuda Isao T. , Iwasaki Hideo
Published: May 2020

Proteins KaiA, KaiB and KaiC constitute a biochemical circadian oscillator in the cyanobacterium Synechococcus elongatus. It has been reported kaiA inactivation completely abolishes circadian oscillations. However, we show here that kaiBC promoter activity exhibits a damped, low-amplitude oscillation with a period of approximately 24 h in kaiA-inactivated strains. The damped rhythm resonates with external cycles with a period of 24–26 h, indicating that its natural frequency is similar to that of the circadian clock. Double-mutation experiments reveal that kaiC, kaiB, and sasA (encoding a KaiC-binding histidine kinase) are all required for the damped oscillation. Further analysis suggests that the kaiA-less damped transcriptional rhythm requires KaiB-KaiC complex formation and the transcription-translation feedback loop, but not the KaiC phosphorylation cycle. Our results provide insights into mechanisms that could potentially underlie the diurnal/circadian behaviors observed in other bacterial species that possess kaiB and kaiC homologues but lack a kaiA homologue.
Evolutionary conserved NSL complex/BRD4 axis controls transcription activation via histone acetylation
Authors: Gaub Aline , Sheikh Bilal N. , Basilicata M. Felicia , Vincent Marie , Nizon Mathilde , Colson Cindy , Bird Matthew J. , Bradner James E. , Thevenon Julien , Boutros Michael , Akhtar Asifa
Published: May 2020

Cells rely on a diverse repertoire of genes for maintaining homeostasis, but the transcriptional networks underlying their expression remain poorly understood. The MOF acetyltransferase-containing Non-Specific Lethal (NSL) complex is a broad transcription regulator. It is essential in Drosophila, and haploinsufficiency of the human KANSL1 subunit results in the Koolen-de Vries syndrome. Here, we perform a genome-wide RNAi screen and identify the BET protein BRD4 as an evolutionary conserved co-factor of the NSL complex. Using Drosophila and mouse embryonic stem cells, we characterise a recruitment hierarchy, where NSL-deposited histone acetylation enables BRD4 recruitment for transcription of constitutively active genes. Transcriptome analyses in Koolen-de Vries patient-derived fibroblasts reveals perturbations with a cellular homeostasis signature that are evoked by the NSL complex/BRD4 axis. We propose that BRD4 represents a conserved bridge between the NSL complex and transcription activation, and provide a new perspective in the understanding of their functions in healthy and diseased states.
Author Correction: Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality
Authors: Sachdeva Mohit , Busser Brian W. , Temburni Sonal , Jahangiri Billal , Gautron Anne-Sophie , Maréchal Alan , Juillerat Alexandre , Williams Alan , Depil Stéphane , Duchateau Philippe , Poirot Laurent , Valton Julien
Published: May 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Surface processes forcing on extensional rock melting
Authors: Sternai Pietro
Published: May 2020

Surface processes and magmatism condition the structural evolution of continental rifts and passive margins through mechanical and thermal effects on the lithosphere rheology. However, their inter-relationships in extensional settings are largely unknown. Here, I use coupled thermo-mechanical geodynamic and landscape evolution numerical modeling to assess the links between erosion of rift shoulders, sedimentation within the rift basin and extensional rock melting. Results suggest that, when the crust is thinner than ~40 km, the extension rate is slower than ~2 cm/yr and the mantle potential temperature is below ~1230 °C, efficient surface processes may double crustal melting by Moho lowering and inhibit mantle decompression melting by ~50% through sediment loading within the rift basin. It is thus likely that surface processes significantly influenced the magmatic activity of a number of extensional settings worldwide – e.g. the Mediterranean, the Gulf of California, the Iberia-Newfoundland margin, and the South China Sea. Because magmatism and surface processes affect jointly the geological carbon cycle, the surface processes forcing on extensional rock melting investigated here involves an additional means of linkage between plate tectonics and climate changes.
Pregnancy rates after slow-release insemination (SRI) and standard bolus intrauterine insemination (IUI) – A multicentre randomised, controlled trial
Authors: Marschalek Julian , Egarter Christian , Vytiska-Binsdorfer Elisabeth , Obruca Andreas , Campbell Jackie , Harris Philip , van Santen Maarten , Lesoine Bernd , Ott Johannes , Franz Maximilian
Published: May 2020

This multicentre, randomised, controlled cross-over trial was designed to investigate the effect of intra-uterine slow-release insemination (SRI) on pregnancy rates in women with confirmed infertility or the need for semen donation who were eligible for standard bolus intra-uterine insemination (IUI). Data for a total of 182 women were analysed after randomisation to receive IUI (n = 96) or SRI (n = 86) first. The primary outcome was serological pregnancy defined by a positive beta human chorionic gonadotropin test, two weeks after insemination. Patients who did not conceive after the first cycle switched to the alternative technique for the second cycle: 44 women switched to IUI and 58 switched to SRI. In total, there were 284 treatment cycles (IUI: n = 140; SRI: n = 144). Pregnancy rates following SRI and IUI were 13.2% and 10.0%, respectively, which was not statistically significant (p = 0.202). A statistically significant difference in pregnancy rates for SRI versus IUI was detected in women aged under 35 years. In this subgroup, the pregnancy rate with SRI was 17% compared to 7% with IUI (relative risk 2.33; p = 0.032) across both cycles. These results support the hypothesis that the pregnancy rate might be improved with SRI compared to standard bolus IUI, especially in women aged under 35 years.
Deep learning-based decision support system for the diagnosis of neoplastic gallbladder polyps on ultrasonography: Preliminary results
Authors: Jeong Younbeom , Kim Jung Hoon , Chae Hee-Dong , Park Sae-Jin , Bae Jae Seok , Joo Ijin , Han Joon Koo
Published: May 2020

Ultrasonography (US) has been considered image of choice for gallbladder (GB) polyp, however, it had limitations in differentiating between nonneoplastic polyps and neoplastic polyps. We developed and investigated the usefulness of a deep learning-based decision support system (DL-DSS) for the differential diagnosis of GB polyps on US. We retrospectively collected 535 patients, and they were divided into the development dataset (n = 437) and test dataset (n = 98). The binary classification convolutional neural network model was developed by transfer learning. Using the test dataset, three radiologists with different experience levels retrospectively graded the possibility of a neoplastic polyp using a 5-point confidence scale. The reviewers were requested to re-evaluate their grades using the DL-DSS assistant. The areas under the curve (AUCs) of three reviewers were 0.94, 0.78, and 0.87. The DL-DSS alone showed an AUC of 0.92. With the DL-DSS assistant, the AUCs of the reviewer’s improved to 0.95, 0.91, and 0.91. Also, the specificity of the reviewers was improved (65.1–85.7 to 71.4–93.7). The intraclass correlation coefficient (ICC) improved from 0.87 to 0.93. In conclusion, DL-DSS could be used as an assistant tool to decrease the gap between reviewers and to reduce the false positive rate.