bluuebunny/crossref_metadata_2025 huggingface dataset:
Faunal composition and paleoenvironmental reconstruction of a Middle–Late Triassic boundary assemblage in the Pyrenean basin (Catalonia, NE Spain)
Authors: Garcia-Artigas Ruben , Mercedes-Martín Ramon , Cartanyà Joan , Bolet Arnau , Riccetto Marc , Fortuny Josep
Published: November 2021

The Ladinian–Carnian transition in the Tethys domain was accompanied by an important environmental change representing a milestone in the climate evolution of the Triassic. However, estimations on paleodiversity composition and paleoenvironmental conditions across this interval are scarce in marine settings due to the lack of fossil-bearing successions. In this work, a refined paleontological and sedimentological study has allowed us to better characterize a well-preserved marine ?Ladinian–Carnian carbonate succession in the South Central Pyrenees (Odèn site, Catalonia, NE Spain). Vertebrate faunas include numerous actinopterygian specimens, forming an assemblage composed of at least four taxa:Peltopleuruscf.P. nuptialisLombardo, 1999,Saurichthyssp.,Colobodus giganteus(Beltan, 1972), and an indeterminate halecomorph. Specimens belonging to the genusPeltopleurusare dominant; the long-snoutedSaurichthys, the halecomorph, and the large-bodiedColobodus giganteusare less abundant. Tetrapod remains are scarcely present and are assigned to sauropterygians. Invertebrate faunas include bivalves (Pseudocorbula gregaria[Münster in Goldfuss, 1838]) and brachiopods (Lingulasp.). The fossil assemblage was recovered from organic-rich laminated silty mudstone layers. Sedimentological and textural analyses suggest that fossil biotas were deposited below the fair-weather wave base in shallow subtidal coastal settings. These environments were sporadically sourced by silt/clay. The age of the Odèn site, on the basis of the recovered fauna, is assigned to the ?late Ladinian–middle Carnian (Middle–Late Triassic), which is in agreement with previously published ages based on palynomorph data.

The refined integration of paleontological, sedimentological, and biostratigraphic data from the Odèn site and other vertebrate-bearing localities in the Tethys domain can help better constrain the paleoenvironmental conditions and paleogeographical configuration impacting ecosystem diversity during the late Ladinian–Carnian interval.
Self-protection as an adaptive female strategy
Authors: Benenson Joyce F. , Webb Christine E. , Wrangham Richard W.
Published: November 2021

Many male traits are well explained by sexual selection theory as adaptations to mating competition and mate choice, whereas no unifying theory explains traits expressed more in females. Anne Campbell's “staying alive” theory proposed that human females produce stronger self-protective reactions than males to aggressive threats because self-protection tends to have higher fitness value for females than males. We examined whether Campbell's theory has more general applicability by considering whether human females respond with greater self-protectiveness than males to other threats beyond aggression. We searched the literature for physiological, behavioral, and emotional responses to major physical and social threats, and found consistent support for females' responding with greater self-protectiveness than males. Females mount stronger immune responses to many pathogens; experience a lower threshold to detect, and lesser tolerance of, pain; awaken more frequently at night; express greater concern about physically dangerous stimuli; exert more effort to avoid social conflicts; exhibit a personality style more focused on life's dangers; react to threats with greater fear, disgust, and sadness; and develop more threat-based clinical conditions than males. Our findings suggest that in relation to threat, human females have relatively heightened protective reactions compared to males. The pervasiveness of this result across multiple domains suggests that general mechanisms might exist underlying females' unique adaptations. An understanding of such processes would enhance knowledge of female health and well-being.
Assembling ‘indigeneity’ through musical practices: translocal circulations, ‘tradition’, and place in Otavalo (Ecuadorian Andes)
Authors: Voirol Jérémie
Published: November 2021

This article addresses the relation between Andean ‘traditional music’ and circulations of people, objects, ideas and sounds. Although many studies on Andean indigenous music have explored such circulations, scholars still tend to understand musical practices in terms of ‘cultures’. The case of indigenous music from Otavalo, in the Ecuadorian Andes, encourages us to go beyond this approach. I make two arguments. First, by conceiving of the translocal/transnational flows that have shaped ‘traditional music’ from Otavalo through the concepts of ‘network’ and ‘music world’, I unsettle the link – underlying previous approaches – between a specific people, music and place. Second, through the concepts of ‘assemblage’ and ‘mediation’, I closely look at processes of ‘traditionalisation’ and ‘indigenisation’ to show how, in the context of multiple circulations, social actors nevertheless produce a specific link between people, music and place in order to make a musical practice ‘traditional’ and/or ‘indigenous’.
Integration of a Palliative Approach in the Care of Older Adults with Dementia in Primary Care Settings: A Scoping Review
Authors: Vellani Shirin , Puts Martine , Iaboni Andrea , Degan Christine , McGilton Katherine S.
Published: November 2021

A palliative approach to care aims to meet the needs of patients and caregivers throughout a chronic disease trajectory and can be delivered by non-palliative specialists. There is an important gap in understanding the perspectives and experiences of primary care providers on an integrated palliative approach in dementia care and the impact of existing programs and models to this end. To address these, we undertook a scoping review. We searched five databases; and used descriptive numerical summary and narrative synthesizing approaches for data analysis. We found that: (1) difficulty with prognostication and a lack of interdisciplinary and intersectoral collaboration are obstacles to using a palliative approach in primary care; and (2) a palliative approach results in statistically and clinically significant impacts on community-dwelling individuals, specifically those with later stages of dementia. There is a need for high-quality research studies examining the integrated palliative approach models and initiation of these models sooner in the care trajectory for persons living with mild and moderate stages of dementia in the community.
Inferring the COVID-19 infection fatality rate in the community-dwelling population: a simple Bayesian evidence synthesis of seroprevalence study data and imprecise mortality data
Authors: Campbell Harlan , Gustafson Paul
Published: November 2021

Estimating the coronavirus disease-2019 (COVID-19) infection fatality rate (IFR) has proven to be particularly challenging –and rather controversial– due to the fact that both the data on deaths and the data on the number of individuals infected are subject to many different biases. We consider a Bayesian evidence synthesis approach which, while simple enough for researchers to understand and use, accounts for many important sources of uncertainty inherent in both the seroprevalence and mortality data. With the understanding that the results of one's evidence synthesis analysis may be largely driven by which studies are included and which are excluded, we conduct two separate parallel analyses based on two lists of eligible studies obtained from two different research teams. The results from both analyses are rather similar. With the first analysis, we estimate the COVID-19 IFR to be 0.31% [95% credible interval (CrI) of (0.16%, 0.53%)] for a typical community-dwelling population where 9% of the population is aged over 65 years and where the gross-domestic-product at purchasing-power-parity (GDP at PPP) per capita is $17.8k (the approximate worldwide average). With the second analysis, we obtain 0.32% [95% CrI of (0.19%, 0.47%)]. Our results suggest that, as one might expect, lower IFRs are associated with younger populations (and may also be associated with wealthier populations). For a typical community-dwelling population with the age and wealth of the United States we obtain IFR estimates of 0.43% and 0.41%; and with the age and wealth of the European Union, we obtain IFR estimates of 0.67% and 0.51%.
Comparison of Doty and McGoon techniques for surgical reconstruction of congenital supravalvular aortic stenosis
Authors: Biçer Mehmet , Dedemoğlu Mehmet , Korun Oktay , Altın Hüsnü F. , Yurdakök Okan , Çiçek Murat , Özdemir Fatih , Selçuk Arif , Altuntaş Yasemin , Yücel Ilker K. , Şaşmazel Ahmet , Aydemir Numan A.
Published: November 2021

Background:

We aimed to compare the results of two surgical methods for the treatment of congenital supravalvular aortic stenosis.

Methods:

From May 2004 to January 2020, 29 patients underwent surgical repair for supravalvular aportic stenosis in a single centre. The perioperative evaluation of the patients was retrospectively reviewed.

Results:

Fifteen (51.7%) and 14 (48.2%) patients were treated with the Doty and the McGoon methods, respectively. The median age of our cohort was 4.5 (3.0–9.9) years. Ten (34.5%) patients had Williams–Beuren syndrome, and pulmonary stenosis was observed in 12 (41.3%) patients. The median follow-up time was 2.5 (0.7–7.3) years. On follow-up, five patients had residual stenosis with the McGoon technique and one with the Doty technique (p = 0.05). One patient died early in the post-operative period in the Doty group, and three patients were re-operated on due to restenosis in the McGoon group. Freedom from re-operation in the Doty group at 1, 3, 5, and 10 years was 100%. In the McGoon group, freedom from re-operation rates at the 1-, 3-, and 7-year follow-up were 100, 88.9, and 44.4%, respectively (p = 0.08).

Conclusion:

Our results with both surgical techniques suggest that supravalvular aortic stenosis can be treated with good results. The Doty method provided better relief for the supravalvular aortic segment, considering the residual stenosis and the re-operation rates.
The role of international humanitarian law in the search for peace: Lessons from Colombia
Authors: Rojas-Orozco César
Published: November 2021

International humanitarian law (IHL) has traditionally been seen as a legal framework regulating armed hostilities, having little to do with peace. However, recent peacemaking and peacebuilding practice has consistently relied on IHL to frame peace efforts, mainly in non-international armed conflicts. This article explores the relationship between IHL and peace, looking at practice in Colombia, where IHL has been used in a creative way as a means to build trust, facilitate peace negotiations and enforce the resulting peace agreement. Looking at this case, the article offers general insights on how IHL can facilitate the end of conflict and reintegration, frame accountability and reparation, and shield peace deals under a framework in which both State and non-State actors can find a common bargaining zone in their search for peace.
Kopfarbeit in guten Händen
Authors: Kubat Heike , Schulze Elke , Feurer Ima
Published: November 2021

Das Fachbuch für die Therapie craniocervicaler Syndrome nach dem CCS-Konzept Die Autorinnen arbeiten seit vielen Jahren an der Entwicklung einer adäquaten Untersuchungs- und Behandlungsmethode im Umgang mit Beschwerden in der Region von Halswirbelsäule und Kopf (craniocervicale Syndrome) wie z.B. Schwindel, Kiefergelenkbeschwerden, Kopfschmerzen und Migräne. Aus ihren Erkenntnissen ist das CCS-Konzept entstanden (www.ccs-konzept.com), mit der von ihnen entwickelten Testbatterie, mit der die verschiedenen Beschwerdebilder gemeinsam untersucht werden können. Craniocervikale Beschwerdebilder sind vielfältig, Untersuchung und Behandlung erfordern eine strukturierte und spezialisierte Vorgehensweise. Ziel des Fachbuches ist es, die Behandler zu einer evidenzbasierten, patientenzentrierten Therapie zu befähigen. Aufbauend auf Kenntnis und Verständnis von Krankheitsbildern und craniocervicalen Dysfunktionen führt das Fachbuch durch den therapeutischen Prozess von Anamnese, Inspektion, Funktionstests aus der Testbatterie, weiterführender Untersuchung, Therapieplanung und -durchführung, ergänzt durch zahlreiche Anmerkungen, Fallbeispiele, Anamnese- und Befundbogen. Dies gelingt auf der Grundlage der folgenden Schwerpunkte: Craniocervicale Syndrome Clinical-Reasoning-Prozesse Durchführung von Tests Beschreibung von Behandlungsmethoden Vestibuläre Rehabilitation Interdisziplinäre Zusammenarbeit
The IL-3, IL-5, and GM-CSF common receptor beta chain mediates oncogenic activity of FLT3-ITD-positive AML
Authors: Charlet Anne , Kappenstein Max , Keye Philip , Kläsener Kathrin , Endres Cornelia , Poggio Teresa , Gorantla Sivahari P. , Kreutmair Stefanie , Sänger Jana , Illert Anna L. , Miething Cornelius , Reth Michael , Duyster Justus , Rummelt Christoph , von Bubnoff Nikolas
Published: November 2021

FLT3-ITD is the most predominant mutation in AML being expressed in about one-third of AML patients and is associated with a poor prognosis. Efforts to better understand FLT3-ITD downstream signaling to possibly improve therapy response are needed. We have previously described FLT3-ITD-dependent phosphorylation of CSF2RB, the common receptor beta chain of IL-3, IL-5, and GM-CSF, and therefore examined its significance for FLT3-ITD-dependent oncogenic signaling and transformation. We discovered that FLT3-ITD directly binds to CSF2RB in AML cell lines and blasts isolated from AML patients. A knockdown of CSF2RB in FLT3-ITD positive AML cell lines as well as in a xenograft model decreased STAT5 phosphorylation, attenuated cell proliferation, and sensitized to FLT3 inhibition. Bone marrow from CSF2RB-deficient mice transfected with FLT3-ITD displayed decreased colony formation capacity and delayed disease onset together with increased survival upon transplantation into lethally irradiated mice. FLT3-ITD-dependent CSF2RB phosphorylation required phosphorylation of the FLT3 juxtamembrane domain at tyrosines 589 or 591, whereas the ITD insertion site and sequence were of no relevance. Our results demonstrate that CSF2RB participates in FLT3-ITD-dependent oncogenic signaling and transformation in vitro and in vivo. Thus, CSF2RB constitutes a rational treatment target in FLT3-ITD-positive AML.
Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior
Authors: Gomez Juan L. , Bonaventura Jordi , Keighron Jacqueline , Wright Kelsey M. , Marable Dondre L. , Rodriguez Lionel A. , Lam Sherry , Carlton Meghan L. , Ellis Randall J. , Jordan Chloe J. , Bi Guo-hua , Solis Oscar , Pignatelli Marco , Bannon Michael J. , Xi Zheng-Xiong , Tanda Gianluigi , Michaelides Michael
Published: November 2021

Cocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc (Zn2+) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that Zn2+concentrations in postmortem brain (caudate) tissue from humans who died of cocaine overdose were significantly lower than in control subjects. Moreover, the level of striatal Zn2+content in these subjects negatively correlated with plasma levels of benzoylecgonine, a cocaine metabolite indicative of recent use. In mice, repeated cocaine exposure increased synaptic Zn2+concentrations in the caudate putamen (CPu) and nucleus accumbens (NAc). Cocaine-induced increases in Zn2+were dependent on the Zn2+transporter 3 (ZnT3), a neuronal Zn2+transporter localized to synaptic vesicle membranes, as ZnT3 knockout (KO) mice were insensitive to cocaine-induced increases in striatal Zn2+. ZnT3 KO mice showed significantly lower electrically evoked DA release and greater DA clearance when exposed to cocaine compared to controls. ZnT3 KO mice also displayed significant reductions in cocaine locomotor sensitization, conditioned place preference (CPP), self-administration, and reinstatement compared to control mice and were insensitive to cocaine-induced increases in striatal DAT binding. Finally, dietary Zn2+deficiency in mice resulted in decreased striatal Zn2+content, cocaine locomotor sensitization, CPP, and striatal DAT binding. These results indicate that cocaine increases synaptic Zn2+release and turnover/metabolism in the striatum, and that synaptically released Zn2+potentiates the effects of cocaine on striatal DA neurotransmission and behavior and is required for cocaine-primed reinstatement. In sum, these findings reveal new insights into cocaine’s pharmacological mechanism of action and suggest that Zn2+may serve as an environmentally derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders.
Association between maternal depression during pregnancy and newborn DNA methylation
Authors: Drzymalla Emily , Gladish Nicole , Koen Nastassja , Epstein Michael P. , Kobor Michael S. , Zar Heather J. , Stein Dan J. , Hüls Anke
Published: November 2021

Around 15–65% of women globally experience depression during pregnancy, prevalence being particularly high in low- and middle-income countries. Prenatal depression has been associated with adverse birth and child development outcomes. DNA methylation (DNAm) may aid in understanding this association. In this project, we analyzed associations between prenatal depression and DNAm from cord blood from participants of the South African Drakenstein Child Health Study. We examined DNAm in an epigenome-wide association study (EWAS) of 248 mother-child pairs. DNAm was measured using the Infinium MethylationEPIC (N = 145) and the Infinium HumanMethylation450 (N = 103) arrays. Prenatal depression scores, obtained with the Edinburgh Postnatal Depression Scale (EPDS) and the Beck Depression Inventory-II (BDI-II), were analyzed as continuous and dichotomized variables. We used linear robust models to estimate associations between depression and newborn DNAm, adjusted for measured (smoking status, household income, sex, preterm birth, cell type proportions, and genetic principal components) and unmeasured confounding using Cate and Bacon algorithms. Bonferroni correction was used to adjust for multiple testing. DMRcate and dmrff were used to test for differentially methylated regions (DMRs). Differential DNAm was significantly associated with BDI-II variables, in cg16473797 (Δ beta = −1.10E-02, p = 6.87E-08), cg23262030 (Δ beta per BDI-II total IQR = 1.47E-03, p = 1.18E-07), and cg04859497 (Δ beta = −6.42E-02, p = 1.06E-09). Five DMRs were associated with at least two depression variables. Further studies are needed to replicate these findings and investigate their biological impact.
Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder
Authors: Doss Manoj K. , Považan Michal , Rosenberg Monica D. , Sepeda Nathan D. , Davis Alan K. , Finan Patrick H. , Smith Gwenn S. , Pekar James J. , Barker Peter B. , Griffiths Roland R. , Barrett Frederick S.
Published: November 2021

Psilocybin has shown promise for the treatment of mood disorders, which are often accompanied by cognitive dysfunction including cognitive rigidity. Recent studies have proposed neuropsychoplastogenic effects as mechanisms underlying the enduring therapeutic effects of psilocybin. In an open-label study of 24 patients with major depressive disorder, we tested the enduring effects of psilocybin therapy on cognitive flexibility (perseverative errors on a set-shifting task), neural flexibility (dynamics of functional connectivity or dFC via functional magnetic resonance imaging), and neurometabolite concentrations (via magnetic resonance spectroscopy) in brain regions supporting cognitive flexibility and implicated in acute psilocybin effects (e.g., the anterior cingulate cortex, or ACC). Psilocybin therapy increased cognitive flexibility for at least 4 weeks post-treatment, though these improvements were not correlated with the previously reported antidepressant effects. One week after psilocybin therapy, glutamate and N-acetylaspartate concentrations were decreased in the ACC, and dFC was increased between the ACC and the posterior cingulate cortex (PCC). Surprisingly, greater increases in dFC between the ACC and PCC were associated with less improvement in cognitive flexibility after psilocybin therapy. Connectome-based predictive modeling demonstrated that baseline dFC emanating from the ACC predicted improvements in cognitive flexibility. In these models, greater baseline dFC was associated with better baseline cognitive flexibility but less improvement in cognitive flexibility. These findings suggest a nuanced relationship between cognitive and neural flexibility. Whereas some enduring increases in neural dynamics may allow for shifting out of a maladaptively rigid state, larger persisting increases in neural dynamics may be of less benefit to psilocybin therapy.
RelA/MicroRNA-30a/NLRP3 signal axis is involved in rheumatoid arthritis via regulating NLRP3 inflammasome in macrophages
Authors: Yang Qiudong , Zhao Wenhua , Chen Yuyi , Chen Yue , Shi Jiali , Qin Ran , Wang Hua , Wang Ruixia , Yuan Hua , Sun Wen
Published: November 2021

NLRP3 inflammasome plays an important role in the pathogenesis of rheumatoid arthritis (RA). However, the post-transcriptional regulation of NLRP3 expression by miRNA in synovial macrophages is still not well understood. The aim of the study is to elucidate the mechanisms of RA with the focus on miRNAs mediated post-transcriptional regulation of the NLRP3 inflammasome. Here, we used NLRP3-deficient mice (NLRP3KO) to cross with TNFα-transgenic mice (TNFTG) to generate NLRP3KO/TNFTG mice, and compared their joint phenotypes with those of their TNFTG and wild-type (WT) littermates at 5 months of age. In comparison to WT mice, articular bone volume and cartilage area are decreased, whereas inflammed area, eroded surface, ALP+ osteoblast number, TRAP+ osteoclast number, and the areas of RelA+F4/80+, Caspase-1+F4/80+, IL-1β+F4/80+ synoviocytes are increased in the TNFTG mice. Knockout of NLRP3 ameliorates joint inflammation and bone damage in TNFTG mice. Further, in TNFα-primed BMDMs, RelA positively regulates NLRP3 expression, but negatively regulates miR-30a. Additionally, miR-30a negatively mediates NLRP3 expression by directly binding to its 3ʹ UTR, suggesting a miR-30a-mediated feedforward loop acting on NLRP3. Finally, intra-articular injection of AAV-miR-30a inhibits NLRP3 inflammasome activation, reduces joint inflammation, and attenuates bone damage in TNFTG mice. Thus, RelA/miR-30a/NLRP3 signal axis is involved in RA through regulating NLRP3 Inflammasome in macrophages.
Biased activation of β2-AR/Gi/GRK2 signal pathway attenuated β1-AR sustained activation induced by β1-adrenergic receptor autoantibody
Authors: Chen Hao , Cao Ning , Wang Li , Wu Ye , Wei Haojie , Li Yuming , Zhang Youyi , Zhang Suli , Liu Huirong
Published: November 2021

Heart failure is the terminal stage of many cardiac diseases, in which β1-adrenoceptor (β1-AR) autoantibody (β1-AA) has a causative role. By continuously activating β1-AR, β1-AA can induce cytotoxicity, leading to cardiomyocyte apoptosis and heart dysfunction. However, the mechanism underlying the persistent activation of β1-AR by β1-AA is not fully understood. Receptor endocytosis has a critical role in terminating signals over time. β2-adrenoceptor (β2-AR) is involved in the regulation of β1-AR signaling. This research aimed to clarify the mechanism of the β1-AA-induced sustained activation of β1-AR and explore the role of the β2-AR/Gi-signaling pathway in this process. The beating frequency of neonatal rat cardiomyocytes, cyclic adenosine monophosphate content, and intracellular Ca2+ levels were examined to detect the activation of β1-AA. Total internal reflection fluorescence microscopy was used to detect the endocytosis of β1-AR. ICI118551 was used to assess β2-AR/Gi function in β1-AR sustained activation induced by β1-AA in vitro and in vivo. Monoclonal β1-AA derived from a mouse hybridoma could continuously activate β1-AR. β1-AA-restricted β1-AR endocytosis, which was reversed by overexpressing the endocytosis scaffold protein β-arrestin1/2, resulting in the cessation of β1-AR signaling. β2-AR could promote β1-AR endocytosis, as demonstrated by overexpressing/interfering with β2-AR in HL-1 cells, whereas β1-AA inhibited the binding of β2-AR to β1-AR, as determined by surface plasmon resonance. ICI118551 biasedly activated the β2-AR/Gi/G protein-coupled receptor kinase 2 (GRK2) pathway, leading to the arrest of limited endocytosis and continuous activation of β1-AR by β1-AA in vitro. In vivo, ICI118551 treatment attenuated myocardial fiber rupture and left ventricular dysfunction in β1-AA-positive mice. This study showed that β1-AA continuously activated β1-AR by inhibiting receptor endocytosis. Biased activation of the β2-AR/Gi/GRK2 signaling pathway could promote β1-AR endocytosis restricted by β1-AA, terminate signal transduction, and alleviate heart damage.
HSD17B6 downregulation predicts poor prognosis and drives tumor progression via activating Akt signaling pathway in lung adenocarcinoma
Authors: Tian Tian , Hong Fu , Wang Zhiwen , Hu Jiaru , Chen Ni , Lv Lei , Yi Qiyi
Published: November 2021

Lung adenocarcinoma is one of the most frequent tumor subtypes, involving changes in a variety of oncogenes and tumor suppressor genes. Hydroxysteroid 17-Beta Dehydrogenase 6 (HSD17B6) could synthetize dihydrotestosterone, abnormal levels of which are associated with progression of multiple tumors. Previously, we showed that HSD17B6 inhibits malignant progression of hepatocellular carcinoma. However, the mechanisms underlying inhibiting tumor development by HSD17B6 are not clear. Moreover, its role in lung adenocarcinoma (LUAD) is yet unknown. Here, we investigated its expression profile and biological functions in LUAD. Analysis of data from the LUAD datasets of TCGA, CPTAC, Oncomine, and GEO revealed that HSD17B6 mRNA and protein expression was frequently lower in LUAD than in non-neoplastic lung tissues, and its low expression correlated significantly with advanced tumor stage, large tumor size, poor tumor differentiation, high tumor grade, smoking, and poor prognosis in LUAD. In addition, its expression was negatively regulated by miR-31-5p in LUAD. HSD17B6 suppressed LUAD cell proliferation, migration, invasion, epithelial–mesenchymal transition (EMT), and radioresistance. Furthermore, HSD17B6 overexpression in LUAD cell lines enhanced PTEN expression and inhibited AKT phosphorylation, inactivating downstream oncogenes like GSK3β, β-catenin, and Cyclin-D independent of dihydrotestosterone, revealing an underlying antitumor mechanism of HSD17B6 in LUAD. Our findings indicate that HSD17B6 may function as a tumor suppressor in LUAD and could be a promising prognostic indicator for LUAD patients, especially for those receiving radiotherapy.
Asymmetric requirement of Dpp/BMP morphogen dispersal in the Drosophila wing disc
Authors: Matsuda Shinya , Schaefer Jonas V. , Mii Yusuke , Hori Yutaro , Bieli Dimitri , Taira Masanori , Plückthun Andreas , Affolter Markus
Published: November 2021

How morphogen gradients control patterning and growth in developing tissues remains largely unknown due to lack of tools manipulating morphogen gradients. Here, we generate two membrane-tethered protein binders that manipulate different aspects of Decapentaplegic (Dpp), a morphogen required for overall patterning and growth of the Drosophila wing. One is “HA trap” based on a single-chain variable fragment (scFv) against the HA tag that traps HA-Dpp to mainly block its dispersal, the other is “Dpp trap” based on a Designed Ankyrin Repeat Protein (DARPin) against Dpp that traps Dpp to block both its dispersal and signaling. Using these tools, we found that, while posterior patterning and growth require Dpp dispersal, anterior patterning and growth largely proceed without Dpp dispersal. We show that dpp transcriptional refinement from an initially uniform to a localized expression and persistent signaling in transient dpp source cells render the anterior compartment robust against the absence of Dpp dispersal. Furthermore, despite a critical requirement of dpp for the overall wing growth, neither Dpp dispersal nor direct signaling is critical for lateral wing growth after wing pouch specification. These results challenge the long-standing dogma that Dpp dispersal is strictly required to control and coordinate overall wing patterning and growth.
An siRNA-guided ARGONAUTE protein directs RNA polymerase V to initiate DNA methylation
Authors: Sigman Meredith J. , Panda Kaushik , Kirchner Rachel , McLain Lauren L. , Payne Hayden , Peasari John Reddy , Husbands Aman Y. , Slotkin R. Keith , McCue Andrea D.
Published: November 2021

In mammals and plants, cytosine DNA methylation is essential for the epigenetic repression of transposable elements and foreign DNA. In plants, DNA methylation is guided by small interfering RNAs (siRNAs) in a self-reinforcing cycle termed RNA-directed DNA methylation (RdDM). RdDM requires the specialized RNA polymerase V (Pol V), and the key unanswered question is how Pol V is first recruited to new target sites without pre-existing DNA methylation. We find that Pol V follows and is dependent on the recruitment of an AGO4-clade ARGONAUTE protein, and any siRNA can guide the ARGONAUTE protein to the new target locus independent of pre-existing DNA methylation. These findings reject long-standing models of RdDM initiation and instead demonstrate that siRNA-guided ARGONAUTE targeting is necessary, sufficient and first to target Pol V recruitment and trigger the cycle of RdDM at a transcribed target locus, thereby establishing epigenetic silencing.
MiR-571 affects the development and progression of liver fibrosis by regulating the Notch3 pathway
Authors: Cong Shuo , Liu Yongmei , Li Yi , Chen Yu , Chen Rui , Zhang Baofang , Yu Lei , Hu Yaxin , Zhao Xueke , Mu Mao , Cheng Mingliang , Huang Zhi
Published: November 2021

Exploring the expression of miR-571 in patients with liver fibrosis and its role in the progression of liver fibrosis. A total of 74 patients with liver fibrosis in our institution from September to December 2018 were collected for study, and the expression of miR-571, Notch3 and Jagged1 in patients with different progressions of liver fibrosis was determined by RT-PCR and Western blot analysis. Set up Notch3 up group and Notch3 down regulated group, RT-PCR and Western blot were used to determine the effect of Notch signaling on the expression of fibrogenic factors. CCK-8, cell scratch assays, Transwell assays, flow cytometry were used to determine the effect of miR-571 on LX-2 proliferation, migration, apoptosis in human stem stellate cells, and RT-PCR, Western blot assays were performed to determine the effect of miR-571 on the Notch3 signaling pathway and the expression of profibrogenic factors. miR-571, Notch3 and Jagged1 are up-regulated in patients with liver fibrosis and is associated with the progression of liver fibrosis. Notch3 signaling pathway can promote the expression of fibroblast in human hepatic stellate cells; miR-571 can inhibit the apoptosis of human hepatic stellate cells, promote cell proliferation and migration; up regulation of miR-571 can promote the expression of Notch3 and Jagged1, and up-regulation of miR-571 also promoted the expression of related fibroblasts. MiR-571 can promote the activation of human stem cell stellate cells and the expression of fibroblast related factors through Notch3 signaling pathway.
Spatial spillover effects from agriculture drive deforestation in Mato Grosso, Brazil
Authors: Kuschnig Nikolas , Cuaresma Jesús Crespo , Krisztin Tamás , Giljum Stefan
Published: November 2021

Deforestation of the Amazon rainforest is a threat to global climate, biodiversity, and many other ecosystem services. In order to address this threat, an understanding of the drivers of deforestation processes is required. Spillover effects and factors that differ across locations and over time play important roles in these processes. They are largely disregarded in applied research and thus in the design of evidence-based policies. In this study, we model connectivity between regions and consider heterogeneous effects to gain more accurate quantitative insights into the inherent complexity of deforestation. We investigate the impacts of agriculture in Mato Grosso, Brazil, for the period 2006–2017 considering spatial spillovers and varying impacts over time and space. Spillovers between municipalities that emanate from croplands in the Amazon appear as the major driver of deforestation, with no direct effects from agriculture in recent years. This suggests a moderate success of the Soy Moratorium and Cattle Agreements, but highlights their inability to address indirect effects. We find that the neglect of the spatial dimension and the assumption of homogeneous impacts lead to distorted inference. Researchers need to be aware of the complex and dynamic processes behind deforestation, in order to facilitate effective policy design.
Genomic characterization between strains selected for death-feigning duration for avoiding attack of a beetle
Authors: Tanaka Keisuke , Sasaki Ken , Matsumura Kentarou , Yajima Shunsuke , Miyatake Takahisa
Published: November 2021

Predator avoidance is an important behavior that affects the degree of adaptation of organisms. We compared the DNA variation of one of the predator-avoidance behaviors, the recently extensively studied "death-feigning behavior”, between the long strain bred for feigning death for a long time and the short strain bred for feigning death for a short time. To clarify how the difference in DNA sequences between the long and short strains corresponds to the physiological characteristics of the death-feigning duration at the transcriptome level, we performed comprehensive and comparative analyses of gene variants in Tribolium castaneum strains using DNA-resequencing. The duration of death feigning involves many gene pathways, including caffeine metabolism, tyrosine metabolism, tryptophan metabolism, metabolism of xenobiotics by cytochrome P450, longevity regulating pathways, and circadian rhythm. Artificial selection based on the duration of death feigning results in the preservation of variants of genes in these pathways in the long strain. This study suggests that many metabolic pathways and related genes may be involved in the decision-making process of anti-predator animal behavior by forming a network in addition to the tyrosine metabolic system, including dopamine, revealed in previous studies.
Osteocrin ameliorates adriamycin nephropathy via p38 mitogen-activated protein kinase inhibition
Authors: Handa Takaya , Mori Keita P. , Ishii Akira , Ohno Shoko , Kanai Yugo , Watanabe-Takano Haruko , Yasoda Akihiro , Kuwabara Takashige , Takahashi Nobuyuki , Mochizuki Naoki , Mukoyama Masashi , Yanagita Motoko , Yokoi Hideki
Published: November 2021

Natriuretic peptides exert multiple effects by binding to natriuretic peptide receptors (NPRs). Osteocrin (OSTN) binds with high affinity to NPR-C, a clearance receptor for natriuretic peptides, and inhibits degradation of natriuretic peptides and consequently enhances guanylyl cyclase-A (GC-A/NPR1) signaling. However, the roles of OSTN in the kidney have not been well clarified. Adriamycin (ADR) nephropathy in wild-type mice showed albuminuria, glomerular basement membrane changes, increased podocyte injuries, infiltration of macrophages, and p38 mitogen-activated protein kinase (MAPK) activation. All these phenotypes were improved in OSTN- transgenic (Tg) mice and NPR3 knockout (KO) mice, with no further improvement in OSTN-Tg/NPR3 KO double mutant mice, indicating that OSTN works through NPR3. On the contrary, OSTN KO mice increased urinary albumin levels, and pharmacological blockade of p38 MAPK in OSTN KO mice ameliorated ADR nephropathy. In vitro, combination treatment with ANP and OSTN, or FR167653, p38 MAPK inhibitor, reduced Ccl2 and Des mRNA expression in murine podocytes (MPC5). OSTN increased intracellular cyclic guanosine monophosphate (cGMP) in MPC5 through GC-A. We have elucidated that circulating OSTN improves ADR nephropathy by enhancing GC-A signaling and consequently suppressing p38 MAPK activation. These results suggest that OSTN could be a promising therapeutic agent for podocyte injury.
Assessing the validity of a cross-platform retinal image segmentation tool in normal and diseased retina
Authors: Alex Varsha , Motevasseli Tahmineh , Freeman William R. , Jayamon Jefy A. , Bartsch Dirk-Uwe G. , Borooah Shyamanga
Published: November 2021

Comparing automated retinal layer segmentation using proprietary software (Heidelberg Spectralis HRA + OCT) and cross-platform Optical Coherence Tomography (OCT) segmentation software (Orion). Image segmentations of normal and diseased (iAMD, DME) eyes were performed using both softwares and then compared to the ‘gold standard’ of manual segmentation. A qualitative assessment and quantitative (layer volume) comparison of segmentations were performed. Segmented images from the two softwares were graded by two masked graders and in cases with difference, a senior retina specialist made a final independent decisive grading. Cross-platform software was significantly better than the proprietary software in the segmentation of NFL and INL layers in Normal eyes. It generated significantly better segmentation only for NFL in iAMD and for INL and OPL layers in DME eyes. In normal eyes, all retinal layer volumes calculated by the two softwares were moderate-strongly correlated except OUTLY. In iAMD eyes, GCIPL, INL, ONL, INLY, TRV layer volumes were moderate-strongly correlated between softwares. In eyes with DME, all layer volume values were moderate-strongly correlated between softwares. Cross-platform software can be used reliably in research settings to study the retinal layers as it compares well against manual segmentation and the commonly used proprietary software for both normal and diseased eyes.
Impact of spaceflight and artificial gravity on sulfur metabolism in mouse liver: sulfur metabolomic and transcriptomic analysis
Authors: Kurosawa Ryo , Sugimoto Ryota , Imai Hiroe , Atsuji Kohei , Yamada Koji , Kawano Yusuke , Ohtsu Iwao , Suzuki Kengo
Published: November 2021

Spaceflight induces hepatic damage, partially owing to oxidative stress caused by the space environment such as microgravity and space radiation. We examined the roles of anti-oxidative sulfur-containing compounds on hepatic damage after spaceflight. We analyzed the livers of mice on board the International Space Station for 30 days. During spaceflight, half of the mice were exposed to artificial earth gravity (1 g) using centrifugation cages. Sulfur-metabolomics of the livers of mice after spaceflight revealed a decrease in sulfur antioxidants (ergothioneine, glutathione, cysteine, taurine, thiamine, etc.) and their intermediates (cysteine sulfonic acid, hercynine,N-acethylserine, serine, etc.) compared to the controls on the ground. Furthermore, RNA-sequencing showed upregulation of gene sets related to oxidative stress and sulfur metabolism, and downregulation of gene sets related to glutathione reducibility in the livers of mice after spaceflight, compared to controls on the ground. These changes were partially mitigated by exposure to 1 g centrifugation. For the first time, we observed a decrease in sulfur antioxidants based on a comprehensive analysis of the livers of mice after spaceflight. Our data suggest that a decrease in sulfur-containing compounds owing to both microgravity and other spaceflight environments (radiation and stressors) contributes to liver damage after spaceflight.
Birth order and prosociality in the early adolescent brain
Authors: Okada Naohiro , Yamamoto Yu , Yahata Noriaki , Morita Susumu , Koshiyama Daisuke , Morita Kentaro , Sawada Kingo , Kanata Sho , Fujikawa Shinya , Sugimoto Noriko , Toriyama Rie , Masaoka Mio , Koike Shinsuke , Araki Tsuyoshi , Kano Yukiko , Endo Kaori , Yamasaki Syudo , Ando Shuntaro , Nishida Atsushi , Hiraiwa-Hasegawa Mariko , Yokoyama Charles , Kasai Kiyoto
Published: November 2021

Birth order is a crucial environmental factor for child development. For example, later-born children are relatively unlikely to feel secure due to sibling competition or diluted parental resources. The positive effect of being earlier-born on cognitive intelligence is well-established. However, whether birth order is linked to social behavior remains controversial, and the neural correlates of birth order effects in adolescence when social cognition develops remain unknown. Here, we explored the birth order effect on prosociality using a large-scale population-based adolescent cohort. Next, since the amygdala is a key region for sociality and environmental stress, we examined amygdala substrates of the association between birth order and prosociality using a subset neuroimaging cohort. We found enhanced prosociality in later-born adolescents (N = 3160), and observed the mediating role of larger amygdala volume (N = 208) and amygdala-prefrontal functional connectivity with sex-selective effects (N = 183). We found that birth order, a non-genetic environmental factor, affects adolescent social development via different neural substrates. Our findings may indicate the later-born people’s adaptive survival strategy in stressful environments.
Novel findings from family-based exome sequencing for children with biliary atresia
Authors: Tran Kien Trung , Le Vinh Sy , Dao Lan Thi Mai , Nguyen Huyen Khanh , Mai Anh Kieu , Nguyen Ha Thi , Ngo Minh Duy , Tran Quynh Anh , Nguyen Liem Thanh
Published: November 2021

Biliary atresia (BA) is a progressive inflammation and fibrosis of the biliary tree characterized by the obstruction of bile flow, which results in liver failure, scarring and cirrhosis. This study aimed to explore the elusive aetiology of BA by conducting whole exome sequencing for 41 children with BA and their parents (35 trios, including 1 family with 2 BA-diagnosed children and 5 child-mother cases). We exclusively identified and validated a total of 28 variants (17 X-linked, 6 de novo and 5 homozygous) in 25 candidate genes from our BA cohort. These variants were among the 10% most deleterious and had a low minor allele frequency against the employed databases: Kinh Vietnamese (KHV), GnomAD and 1000 Genome Project. Interestingly, AMER1, INVS and OCRL variants were found in unrelated probands and were first reported in a BA cohort. Liver specimens and blood samples showed identical variants, suggesting that somatic variants were unlikely to occur during morphogenesis. Consistent with earlier attempts, this study implicated genetic heterogeneity and non-Mendelian inheritance of BA.
A study of sex difference in infant mortality in UK pediatric intensive care admissions over an 11-year period
Authors: Almossawi Ofran , O’Brien Scott , Parslow Roger , Nadel Simon , Palla Luigi
Published: November 2021

Within the UK, child mortality from all causes has declined for all ages over the last three decades. However, distinct inequality remains, as child mortality rates are generally found to be higher in males. A significant proportion of childhood deaths in the UK occur in Paediatric Intensive Care Units (PICU). We studied the association of sex with infant mortality in PICUs. We included all infants (0 to 12 months old) admitted to UK PICUs from 01/01/2005 to 31/12/2015 using the Paediatric Intensive Care Audit Network (PICANet) dataset. We considered first admissions to PICU and fitted a cause-specific-hazard-ratio (CSHR) model, and a logistic model to estimate the adjusted association between sex and mortality in PICU. Pre-defined subgroups were children less than 56-days old, and those with a primary diagnosis of infection. Of 71,243 cases, 1,411/29,520 (4.8%) of females, and 1,809/41,723 (4.3%) of males died. The adjusted male/female CSHR was 0.87 (95%-CI 0.81 to 0.92) representing a 13% higher risk of death for females. The adjusted OR for male to female mortality is 0.86 (95%-CI 0.80 to 0.93). Analyses in subgroups yielded similar findings. In our analysis, female infants have a higher rate of PICU mortality compared to male infants.
Adherence to plant-based dietary patterns in relation to glioma: a case–control study
Authors: Mousavi Seyed Mohammad , Shayanfar Mehdi , Rigi Somaye , Mohammad-Shirazi Minoo , Sharifi Giuve , Esmaillzadeh Ahmad
Published: November 2021

Available evidence suggests a favorable association between adherence to a plant-based diet and disease prevention, but data on the link between such dietary intakes and cancer are scarce. We examined the association between the overall plant-based diet (PDI), healthy plant-based diet (hPDI), and unhealthy plant-based diet (uPDI) and risk of glioma. This case–control study was conducted on 128 newly diagnosed glioma patients, and 256 hospital-based controls. Cases were diagnosed by pathological test and controls were selected from hospitalized people in orthopedic and surgical wards. Dietary intakes were assessed using a validated Block-format 123-items food frequency questionnaire. Scores of plant-based dietary patterns were calculated using the method suggested by Satija et al. After controlling for potential confounders, individuals with higher scores of PDI (OR: 0.54, 95% CI: 0.32–0.91,P-trend < 0.001) and hPDI (OR: 0.32, 95% CI: 0.18–0.57,P-trend < 0.001) had significantly lower odds of glioma compared with those with the lowest scores. This association did not change in the fully adjusted model; such that subjects in the highest tertile of PDI and hPDI were 69% and 71% less likely to have glioma compared with those in the lowest tertile. In contrast, higher scores of uPDI was significantly associated with a greater odds of glioma (OR: 2.85, 95% CI: 1.26–6.47,P-trend = 0.02). Adherence to PDI and hPDI was associated with a lower odds of glioma, while greater adherence to uPDI was directly associated with the likelihood of glioma. Further prospective cohort studies are needed to examine our findings.
Freeze-dried Nannochloropsis oceanica biomass protects eicosapentaenoic acid (EPA) from metabolization in the rumen of lambs
Authors: Vítor Ana C. M. , Francisco Alexandra E. , Silva Joana , Pinho Mário , Huws Sharon A. , Santos-Silva José , Bessa Rui J. B. , Alves Susana P.
Published: November 2021

Eicosapentaenoic acid (EPA) from freeze-dried biomass of Nannochloropsis oceanica microalgae resists ruminal biohydrogenation in vitro, but in vivo demonstration is needed. Therefore, the present study was designed to test the rumen protective effects of N. oceanica in lambs. Twenty-eight lambs were assigned to one of four diets: Control (C); and C diets supplemented with: 1.2% Nannochloropsis sp. oil (O); 12.3% spray-dried N. oceanica (SD); or 9.2% N. oceanica (FD), to achieve 3 g EPA /kg dry matter. Lambs were slaughtered after 3 weeks and digestive contents and ruminal wall samples were collected. EPA concentration in the rumen of lambs fed FD was about 50% higher than lambs fed SD or O diets. Nevertheless, the high levels of EPA in cecum and faeces of animals fed N. oceanica biomass, independently of the drying method, suggests that EPA was not completely released and absorbed in the small intestine. Furthermore, supplementation with EPA sources also affected the ruminal biohydrogenation of C18 fatty acids, mitigating the shift from the t10 biohydrogenation pathways to the t11 pathways compared to the Control diet. Overall, our results demonstrate that FD N. oceanica biomass is a natural rumen-protected source of EPA to ruminants.