bluuebunny/crossref_metadata_2025 huggingface dataset:
Using XFEM to model the effect of different axial compression on the hysteretic behaviour of the flexure‐dominant RC columns
Authors: Yu Jiangtao , Zhan Kaili , Li Lingzhi , Yu Kequan
Published: January 2018

The axial compression ratio has a significant effect on the strength and ductility of reinforced concrete (RC) columns subjected to seismic loads. However, limited numerical models have been found to be able to consider the effect of axial compression ratio in mesoscopic scale. To achieve a sound understanding of the hysteretic mechanism of RC columns with different axial compression ratios, a novel modelling method was developed by employing the following techniques: (a) the extended finite element method for modelling crack initiating and propagating in concrete; (b) the contact algorithm for modelling the crack closure; and (c) the Cartesian type “connector” for modelling the interaction between concrete and steel bars. The effectiveness of the proposed model was validated in macroscopic scale by the results of a previous experimental study. Further analysis indicates that the axial compression ratio controls the axial deformations of RC columns, thus leads to different performances of concrete and steel under seismic loads. Based on the individual flexural contributions of the concrete and the steel bars, the effect of the axial compression ratio and the pinching effect is explained in a finer scale. The analytical results shed some light on the seismic mechanism of RC columns with different axial compression ratios.
Comparison of Adverse Events and Outcomes Between Patients With and Without Drain Insertion After Hepatectomy: A Propensity Score‐Matched, Multicenter, Prospective Observational Cohort Study in Japan (CSGO‐HBP‐001)
Authors: Yamada Terumasa , Gotoh Kunihito , Marubashi Shigeru , Asaoka Tadafumi , Miyamoto Atsushi , Kobayashi Shogo , Eguchi Hidetoshi , Shimizu Junzo , Kim Yongkook , Tsujie Masanori , Noda Takehiro , Yokoyama Shigekazu , Takeda Yutaka , Mori Masaki , Doki Yuichiro , Nagano Hiroaki
Published: January 2018

Background

Adverse events (AEs) after hepatectomy (Hx) have decreased. The aim of this study was to assess the safety of Hx and to identify the risks and benefits of drain insertion.

Methods

From 2010 to 2012, a multicenter, prospective cohort study was conducted in consecutive patients who underwent Hx. Patients who were scheduled to undergo Hx with neither reconstruction of the biliary tract nor concomitant resection of other organs were excluded. AEs were graded based on the Clavien–Dindo classification. Univariate analysis was performed to identify the risks and benefits in all cases and in selected cases matched by propensity score.

Results

This study included 197 patients. AEs occurred in 20 (10.1%). In all cases, no difference in the rate of AE was observed between those with and without drain insertion. Postoperative hospital stay in the group with drains (n = 132) was statistically longer than that in the group without drains (n = 65) (17.7 vs. 11.5 days, P = 0.001). In patients without AE (n = 177), hospital stay in the group with drains was statistically longer than that in the group without drains (14.1 vs. 11.3 days, P < 0.001). In propensity score‐matched cases (41 cases in each group), postoperative hospital stay in the group with drains was also statistically longer than that in the group without drains (17.3 vs. 11.4 days, P = 0.003).

Conclusion

Drain insertion after hepatectomy may lead to longer hospital stay in patients with and without AE.
Post‐operative Complications Following Emergency Operations Performed by Trainee Surgeons: A Retrospective Analysis of Surgical Deaths
Authors: Ferrah Noha , Stephan Karen , Lovell Janaka , Ibrahim Joseph , Beiles Barry
Published: January 2018

Background

Adequate surgical care of patients and concurrent training of residents is achieved in elective procedures through careful case selection and adequate supervision. Whether this applies when trainees are involved in emergency operations remains equivocal. The aim of this study was therefore to compare the risk of post‐operative complications following emergency procedures performed by senior operators compared with supervised trainees.

Methods

This is a retrospective cohort study examining in‐hospital deaths of patients across all surgical specialties who underwent emergency surgery in Australian public hospitals reported to the national surgical mortality audit between 2009 and 2015. Multivariable logistic regression was used to explore whether there was an association between the level of operator experience (senior operator vs trainee) and the occurrence of post‐operative surgical complications following an emergency procedure.

Results

Our population consisted of 6920 patients. There were notable differences between the trainees and senior operator groups; trainees more often operated on patients aged over 80 years, with cardiovascular and neurological risk factors. Senior operators more often operated on very young and obese patients with advanced malignancy and hepatic disease. Supervised trainees had a lower rate of post‐operative complications compared with senior operators; 18% (n = 396) and 25% (n = 1210), respectively (p < 0.05). Operations performed by trainees were associated with an 18% decrease (95% CI 5–29%; p < 0.05) in odds of post‐operative complications compared with senior operators, adjusting for potential confounders.

Conclusions

Contrary to popular belief, our results suggest that supervised trainees safely perform emergency operations, provided that cases are judiciously selected.
Understanding, Recognising and Treating Co-occurring Anxiety in Autism
Authors: Rodgers Jacqui , Ofield A.
Published: January 2018

Purpose of Review

Autistic people are at increased risk of anxiety, with around 50% of autistic adults and children experiencing this debilitating mental health condition. The purpose of this review is to consider some contemporary ideas about underlying mechanisms for anxiety in autism, explore issues in the identification and assessment of anxiety and discuss emerging trends in anxiety interventions for autistic people, before identifying some important next steps in the field.

Recent Findings

Emerging evidence suggests that anxiety may present differently in autism compared to the general population and that whilst CBT holds promise, there may be important differences in neurobiological, affective and cognitive responses to stressors for autistic people, which warrant tailored anxiety models, assessments and interventions.

We conclude that research is needed to develop and evaluate theoretical frameworks, assessment methods and interventions for anxiety in autism, particularly for autistic adults and those with co-occurring intellectual disability.
Novel polymorphisms in TICAM2 and NOD1 associated with tuberculosis progression phenotypes in Ethiopian populations
Authors: Mekonnen E. , Bekele E. , Stein C. M.
Published: January 2018

Background

Infection by Mycobacterium tuberculosis (Mtb) is a necessary but not sufficient cause for tuberculosis (TB). Although numerous studies suggest human genetic variation may influence TB pathogenesis, there is a conspicuous lack of replication, likely due to imprecise phenotype definition. We aimed to replicate novel findings from a Ugandan cohort in Ethiopian populations.

Method

We ascertained TB cases and household controls (n = 292) from three different ethnic groups. Latent Mtb infection was determined using Quantiferon to develop reliable TB progression phenotypes. We sequenced exonic regions of TICAM2 and NOD1.

Result

Significant novel associations were observed between two variants in NOD1 and TB: rs751770147 [unadjusted p = 7.28 × 10−5] and chr7:30477156(T), a novel variant, [unadjusted p = 1.04 × 10−4]. Two SNPs in TICAM2 were nominally associated with TB, including rs2288384 [unadjusted p = 0.003]. Haplotype-based association tests supported the SNP-based results.

Conclusion

We replicated the association of TICAM2 and NOD1 with TB and identified novel genetic associations with TB in Ethiopian populations.
Miniaturization and morphological evolution in Paleozoic relatives of living amphibians: a quantitative approach
Authors: Pérez-Ben Celeste M. , Schoch Rainer R. , Báez Ana M.
Published: January 2018

Miniaturization has been defined as the evolution of extremely small adult size in a lineage. It does not simply imply the decrease of the body size but also involves structural modifications to maintain functional efficiency at a strongly reduced size. Miniaturization has been proposed as a key factor in the origin of several major tetrapod clades. Current hypotheses propose that the living amphibians (lissamphibians) originated within a clade of Paleozoic dwarfed dissorophoid temnospondyls. Morphological traits shared by these small dissorophoids have been interpreted as resulting from constraints imposed by the extreme size reduction, but these statements were based only on qualitative observations. Herein, we assess quantitatively morphological changes in the skull previously associated with miniaturization in the lissamphibian stem lineage by comparing evolutionary and ontogenetic allometries in dissorophoids. Our results show that these features are not comparable to the morphological consequences of extreme size reduction as documented in extant miniature amphibians, but instead they resemble immature conditions of larger temnospondyls. We conclude that the truncation of the ancestral ontogeny, and not constraints related to miniaturization, might have been the factor that played a major role in the morphological evolution of small dissorophoids. Based on our results, we discuss the putative role of miniaturization in the origin of lissamphibians within Dissorophoidea.
Making a Brazilian New Deal: Oliveira Vianna and the Transnational Sources of Brazil's Corporatist Experiment
Authors: TEIXEIRA MELISSA
Published: January 2018

This article explores the legal writings of Brazilian sociologist and jurist Francisco José de Oliveira Vianna to reveal the global context that shaped Brazil's corporatist experiment in the 1930s. From the Labour Ministry, Oliveira Vianna was at the forefront of legal and political debates over how to create corporatist laws and institutions. He was often cast as an authoritarian and retrograde thinker, yet this article looks beyond those categories to examine how his engagement with the US New Deal inserted corporatism into global debates over the role of the state in economic recovery and social welfare.
Sex- and age patterns in incidence of infectious diseases in Germany: analyses of surveillance records over a 13-year period (2001–2013)
Authors: Walter F. , Ott J. J. , Claus H. , Krause G.
Published: January 2018

Sex differences in the incidence of infections may indicate different risk factors and behaviour but have not been analysed across pathogens. Based on 3.96 million records of 33 pathogens in Germany, notified from 2001 to 2013, we applied Poisson regression to generate age-standardised incidence rate ratios and assessed their distribution across age and sex. The following trends became apparent: (a) pathogens with male incidence preponderance at infant and child age (meningococcal disease (incidence rate ratio (IRR) = 1.19, 95% CI 1.03–1.38, age = 0–4); influenza (IRR = 1.09, 95% CI 1.06–1.13, age = 0–4)), (b) pathogens with sex-switch in incidence preponderance at puberty (e.g. norovirus (IRR = 1.10, 95% CI 1.02–1.19 in age = 5–14, IRR = 0.96, 95% CI 0.93–0.99, age ⩾ 60), (c) pathogens with general male incidence preponderance (bacterial/parasitic infections with campylobacter, Yersinia and Giardia), (d) pathogens with male incidence preponderance at juvenile and adult age (sexually transmitted or vector-borne infections (combined-IRR = 2.53, 95% CI 2.36–2.71, age = 15–59), (e) pathogens with male preponderance at older age (tick-borne encephalitis - IRR = 2.75, 95% CI 1.21–6.24, listeriosis - IRR = 2.06, 95% CI 1.38–3.06, age ⩾ 60). Risk factor concepts only partly serve to interpret similarities of grouped infections, i.e. transmission-related explanations and sex-specific exposures not consistently explain the pattern of food-borne infections (b). Sex-specific differences in infectious disease incidence are well acknowledged regarding the sexually transmitted diseases. This has led to designing gender-specific prevention strategies. Our data suggest that for infections with other transmission routes, gender-specific approaches can also be of benefit and importance.
Maternal and neonatal micronutrient levels in newborns with CHD
Authors: Dilli Dilek , Doğan Nazan Neslihan , Örün Utku Arman , Koç Murat , Zenciroğlu Ayşegül , Karademir Selmin , Akduman Hasan
Published: January 2018

Objective

It is suggested that folic acid and/or multivitamins, taken periconceptionally, have a role in the prevention of many congenital anomalies. The aim of this study was to determine the serum micronutrient levels in mother–infant pairs with CHD compared with those with healthy newborns and their mothers.

Methods

Serum levels of folic acid, homocysteine, zinc, vitamin A, vitamin D, and vitamin B12were measured from 108 newborns with CHD (study group) and 103 healthy newborns (control group). The mothers’ micronutrient levels were also measured simultaneously.

Results

When compared with healthy newborns, for both maternal and neonatal data, homocysteine and zinc levels were higher and vitamin D levels were lower in the study group. In multivariate analysis, only maternal high zinc levels were associated with CHD in the newborns (p=0.02, OR: 0.9, 95% CI 0.8–0.9). The results did not change when analysed for truncal anomalies including truncus arteriosus, tetralogy of Fallot, and d-transposition of great arteries. There were positive correlations between maternal and neonatal levels of micronutrients, except vitamin B12.

Conclusion

We thought that high homocysteine and zinc levels and low vitamin D levels in mother–infant pairs might have a role in the aetiopathogenesis of CHD. Large-scale, prospective studies are needed to clarify the role of micronutrients in CHDs.
Inorganic carbon addition stimulates snow algae primary productivity
Authors: Hamilton Trinity L , Havig Jeff R
Published: January 2018

Earth has experienced glacial/interglacial oscillations accompanied by changes in atmospheric CO2 throughout much of its history. Today over 15 million square kilometers of Earth’s land surface is covered in ice including glaciers, ice caps, and ice sheets. Glaciers are teeming with life and supraglacial snow and ice surfaces are often darkened by the presence of photoautotrophic snow algae, resulting in accelerated melt due to lowered albedo. Few studies report the productivity of snow algal communities and the parameters which constrain their growth on supraglacial surfaces—key factors for quantifying biologically induced albedo effects (bio-albedo). We demonstrate that snow algae primary productivity is stimulated by the addition of inorganic carbon. Our results indicate a positive feedback between increasing CO2 and snow algal primary productivity, underscoring the need for robust climate models of past and present glacial/interglacial oscillations to include feedbacks between supraglacial primary productivity, albedo, and atmospheric CO2.
Arsenic trioxide promoting ETosis in acute promyelocytic leukemia through mTOR-regulated autophagy
Authors: Li Tao , Ma Ruishuang , Zhang Yan , Mo Hongdan , Yang Xiaoyan , Hu Shaoshan , Wang Lixiu , Novakovic Valerie A , Chen He , Kou Junjie , Bi Yayan , Yu Bo , Fang Shaohong , Wang Jinghua , Zhou Jin , Shi Jialan
Published: January 2018

Despite the high efficacy and safety of arsenic trioxide (ATO) in treating acute promyelocytic leukemia (APL) and eradicating APL leukemia-initiating cells (LICs), the mechanism underlying its selective cytotoxicity remains elusive. We have recently demonstrated that APL cells undergo a novel cell death program, termed ETosis, through autophagy. However, the role of ETosis in ATO-induced APL LIC eradication remains unclear. For this study, we evaluated the effects of ATO on ETosis and the contributions of drug-induced ETosis to APL LIC eradication. In NB4 cells, ATO primarily increased ETosis at moderate concentrations (0.5–0.75 μM) and stimulated apoptosis at higher doses (1.0–2.0 μM). Furthermore, ATO induced ETosis through mammalian target of rapamycin (mTOR)-dependent autophagy, which was partially regulated by reactive oxygen species. Additionally, rapamycin-enhanced ATO-induced ETosis in NB4 cells and APL cells from newly diagnosed and relapsed patients. In contrast, rapamycin had no effect on apoptosis in these cells. We also noted that PML/RARA oncoprotein was effectively cleared with this combination. Intriguingly, activation of autophagy with rapamycin-enhanced APL LIC eradication clearance by ATO in vitro and in a xenograft APL model, while inhibition of autophagy spared clonogenic cells. Our current results show that ATO exerts antileukemic effects at least partially through ETosis and targets LICs primarily through ETosis. Addition of drugs that target the ETotic pathway could be a promising therapeutic strategy to further eradicate LICs and reduce relapse.
MicroRNA miR-4779 suppresses tumor growth by inducing apoptosis and cell cycle arrest through direct targeting of PAK2 and CCND3
Authors: Koo Kyung Hee , Kwon Heechung
Published: January 2018

Depending on the function of their target genes, microRNAs (miRNAs) act as either tumor suppressors or oncogenes. Therefore, miRNAs represent a novel therapeutic strategy for prevention and management of cancer by targeting of onco-miRNAs or mimicking of tumor suppressor miRNAs. Herein, we identified novel tumor suppressor miRNAs and investigated their molecular mechanisms. To identify novel tumor suppressor miRNAs, we used 532 human miRNA mimic libraries and measured cell viability using MTS assays. The function of miR-4779 was then analyzed using cell cycle analyses and apoptosis, colony forming, and soft agar assays. Target genes of miR-4779 were predicted using TargetScan and miRDB databases and were confirmed using luciferase assays. Levels of miR-4779 and target genes in colon cancer tissue samples from patients were evaluated using qRT-PCR and western blotting analyses. Finally, in vivo tumor suppressive effects of miR-4779 were evaluated in HCT116 xenografts. In this study, miR-4779 inhibited cancer cell growth by inducing apoptosis and cell cycle arrest, and the putative survival factors PAK2 and CCND3 were identified as direct targets of miR-4779. In subsequent experiments, PAK2 knockdown induced cell cycle arrest and CCND3 knockdown induced cell cycle arrest and apoptosis. In addition, miR-4779 suppressed tumor growth and tumorigenesis in an in vivo HCT116 xenograft model. Finally, miR-4779 expression was low in 9 of 10 colon cancer tissues, whereas PAK2 and CCND3 expressions were significantly high in colon cancer tissues. The novel tumor suppressor miR-4779 inhibits cancer cell growth via cell cycle arrest and apoptosis by directly targeting PAK2 and CCND3. The present data indicate the potential of miR-4779 as a therapeutic target for miRNA-based cancer therapy.
Control of primary metabolism by a virulence regulatory network promotes robustness in a plant pathogen
Authors: Peyraud Rémi , Cottret Ludovic , Marmiesse Lucas , Genin Stéphane
Published: January 2018

Robustness is a key system-level property of living organisms to maintain their functions while tolerating perturbations. We investigate here how a regulatory network controlling multiple virulence factors impacts phenotypic robustness of a bacterial plant pathogen. We reconstruct a cell-scale model of Ralstonia solanacearum connecting a genome-scale metabolic network, a virulence macromolecule network, and a virulence regulatory network, which includes 63 regulatory components. We develop in silico methods to quantify phenotypic robustness under a broad set of conditions in high-throughput simulation analyses. This approach reveals that the virulence regulatory network exerts a control of the primary metabolism to promote robustness upon infection. The virulence regulatory network plugs into the primary metabolism mainly through the control of genes likely acquired via horizontal gene transfer, which results in a functional overlay with ancestral genes. These results support the view that robustness may be a selected trait that promotes pathogenic fitness upon infection.
Dual catalysis for enantioselective convergent synthesis of enantiopure vicinal amino alcohols
Authors: Ye Chen-Xi , Melcamu Yared Yohannes , Li Heng-Hui , Cheng Jiang-Tao , Zhang Tian-Tian , Ruan Yuan-Ping , Zheng Xiao , Lu Xin , Huang Pei-Qiang
Published: January 2018

Enantiopure vicinal amino alcohols and derivatives are essential structural motifs in natural products and pharmaceutically active molecules, and serve as main chiral sources in asymmetric synthesis. Currently known asymmetric catalytic protocols for this class of compounds are still rare and often suffer from limited scope of substrates, relatively low regio- or stereoselectivities, thus prompting the development of more effective methodologies. Herein we report a dual catalytic strategy for the convergent enantioselective synthesis of vicinal amino alcohols. The method features a radical-type Zimmerman–Traxler transition state formed from a rare earth metal with a nitrone and an aromatic ketyl radical in the presence of chiral N,N′-dioxide ligands. In addition to high level of enantio- and diastereoselectivities, our synthetic protocol affords advantages of simple operation, mild conditions, high-yielding, and a broad scope of substrates. Furthermore, this protocol has been successfully applied to the concise synthesis of pharmaceutically valuable compounds (e.g., ephedrine and selegiline).
Molecular basis for the specific and multivariant recognitions of RNA substrates by human hnRNP A2/B1
Authors: Wu Baixing , Su Shichen , Patil Deepak P. , Liu Hehua , Gan Jianhua , Jaffrey Samie R. , Ma Jinbiao
Published: January 2018

Human hnRNP A2/B1 is an RNA-binding protein that plays important roles in many biological processes, including maturation, transport, and metabolism of mRNA, and gene regulation of long noncoding RNAs. hnRNP A2/B1 was reported to control the microRNAs sorting to exosomes and promote primary microRNA processing as a potential m6A “reader.” hnRNP A2/B1 contains two RNA recognition motifs that provide sequence-specific recognition of RNA substrates. Here, we determine crystal structures of tandem RRM domains of hnRNP A2/B1 in complex with various RNA substrates, elucidating specific recognitions of AGG and UAG motifs by RRM1 and RRM2 domains, respectively. Further structural and biochemical results demonstrate multivariant binding modes for sequence-diversified RNA substrates, supporting a RNA matchmaker mechanism in hnRNP A2/B1 function. Moreover, our studies in combination with bioinformatic analysis suggest that hnRNP A2/B1 may mediate effects of m6A through a “m6A switch” mechanism, instead of acting as a direct “reader” of m6A modification.
RASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73
Authors: Papaspyropoulos Angelos , Bradley Leanne , Thapa Asmita , Leung Chuen Yan , Toskas Konstantinos , Koennig Delia , Pefani Dafni-Eleftheria , Raso Cinzia , Grou Claudia , Hamilton Garth , Vlahov Nikola , Grawenda Anna , Haider Syed , Chauhan Jagat , Buti Ludovico , Kanapin Alexander , Lu Xin , Buffa Francesca , Dianov Grigory , von Kriegsheim Alex , Matallanas David , Samsonova Anastasia , Zernicka-Goetz Magdalena , O’Neill Eric
Published: January 2018

Transition from pluripotency to differentiation is a pivotal yet poorly understood developmental step. Here, we show that the tumour suppressor RASSF1A is a key player driving the early specification of cell fate. RASSF1A acts as a natural barrier to stem cell self-renewal and iPS cell generation, by switching YAP from an integral component in the β-catenin-TCF pluripotency network to a key factor that promotes differentiation. We demonstrate that epigenetic regulation of the Rassf1A promoter maintains stemness by allowing a quaternary association of YAP–TEAD and β-catenin–TCF3 complexes on the Oct4 distal enhancer. However, during differentiation, promoter demethylation allows GATA1-mediated RASSF1A expression which prevents YAP from contributing to the TEAD/β-catenin–TCF3 complex. Simultaneously, we find that RASSF1A promotes a YAP–p73 transcriptional programme that enables differentiation. Together, our findings demonstrate that RASSF1A mediates transcription factor selection of YAP in stem cells, thereby acting as a functional “switch” between pluripotency and initiation of differentiation.
Dopamine genes are linked to Extraversion and Neuroticism personality traits, but only in demanding climates
Authors: Fischer Ronald , Lee Anna , Verzijden Machteld N.
Published: January 2018

Cross-national differences in personality have long been recognized in the behavioural sciences. However, the origins of such differences are debated. Building on reinforcement sensitivity theories and gene-by-environment interactions, we predict that personality trait phenotypes linked to dopaminergic brain functions (centrally involved in reward processing) diverge most strongly in climatically stressful environments, due to shifts in perceived rewards vs risks. Individuals from populations with a highly efficient dopamine system are biased towards behavioural approach traits (Extraversion and Emotional Stability) due to higher perceived reward values, whereas individuals from populations with a less efficient dopaminergic system are biased towards risk avoidance. In temperate climates, we predict smaller phenotypic differences due to overall weakened reward and risk ratios. We calculated a population-level index of dopamine functioning using 9 commonly investigated genetic polymorphisms encoding dopamine transporters and receptors, derived from a meta-analysis with data from 805 independent samples involving 127,685 participants across 73 societies or territories. We found strong support for the dopamine gene by climatic stress interaction: Population genetic differences in dopamine predicted personality traits at the population level in demanding climates, but not in temperate, less demanding climates, even when controlling for known correlates of personality including wealth and parasite stress.
The motilin agonist erythromycin increases hunger by modulating homeostatic and hedonic brain circuits in healthy women: a randomized, placebo-controlled study
Authors: Zhao Dongxing , Meyer-Gerspach Anne Christin , Deloose Eveline , Iven Julie , Weltens Nathalie , Depoortere Inge , O’daly Owen , Tack Jan , Van Oudenhove Lukas
Published: January 2018

The motilin agonist, erythromycin, induces gastric phase III of the migrating motor complex, which in turn generates hunger peaks. To identify the brain mechanisms underlying these orexigenic effects, 14 healthy women participated in a randomized, placebo-controlled crossover study. Functional magnetic resonance brain images were acquired for 50 minutes interprandially. Intravenous infusion of erythromycin (40 mg) or saline started 10 minutes after the start of scanning. Blood samples (for glucose and hormone levels) and hunger ratings were collected at fixed timepoints. Thirteen volunteers completed the study, without any adverse events. Brain regions involved in homeostatic and hedonic control of appetite and food intake responded to erythromycin, including pregenual anterior cingulate cortex, anterior insula cortex, orbitofrontal cortex, amygdala, caudate, pallidum and putamen bilaterally, right accumbens, hypothalamus, and midbrain. Octanoylated ghrelin levels decreased, whereas both glucose and insulin increased after erythromycin. Hunger were higher after erythromycin, and these differences covaried with the brain response in most of the abovementioned regions. The motilin agonist erythromycin increases hunger by modulating neurocircuitry related to homeostatic and hedonic control of appetite and feeding. These results confirm recent behavioural findings identifying motilin as a key orexigenic hormone in humans, and identify the brain mechanisms underlying its effect.
Chemotherapy drugs cyclophosphamide, cisplatin and doxorubicin induce germ cell loss in an in vitro model of the prepubertal testis
Authors: Smart Ellie , Lopes Federica , Rice Siobhan , Nagy Boglarka , Anderson Richard A. , Mitchell Rod T. , Spears Norah
Published: January 2018

Long term survival rates for childhood cancers is steadily increasing, however cancer survivors can experience fertility problems as a consequence of chemotherapy treatment. This is particularly problematic for young boys, for whom no fertility preservation treatment is yet established. Here, we have determined the effects on prepubertal mouse testis of three commonly used chemotherapy drugs; cyclophosphamide (using its active metabolite phosphoramide mustard), cisplatin and doxorubicin, exposing testicular fragments to a clinically relevant range of concentrations in vitro. All three drugs induced a specific and highly significant loss of germ cells, including spermatogonial stem cells. In contrast, there was no significant effect on somatic cells, for either Sertoli or interstitial cells. Time course analysis of cleaved Caspase-3 expression showed a significant increase in apoptosis eight hours prior to a detectable decrease in germ cell numbers following exposure to phosphoramide mustard or cisplatin, although this pattern was not seen following doxorubicin-exposure. Moreover, analysis of DNA damage at 16 h showed increased γH2AX expression in response to all three drugs. Overall, results show that cisplatin, doxorubicin and cyclophosphamide all specifically induce loss of germ cells, including of spermatogonial stem cells, in the prepubertal mouse testis at concentrations relevant to human therapeutic exposures.
Human mate-choice copying is domain-general social learning
Authors: Street Sally E. , Morgan Thomas J. H. , Thornton Alex , Brown Gillian R. , Laland Kevin N. , Cross Catharine P.
Published: January 2018

Women appear to copy other women’s preferences for men’s faces. This ‘mate-choice copying’ is often taken as evidence of psychological adaptations for processing social information related to mate choice, for which facial information is assumed to be particularly salient. No experiment, however, has directly investigated whether women preferentially copy each other’s face preferences more than other preferences. Further, because prior experimental studies used artificial social information, the effect of real social information on attractiveness preferences is unknown. We collected attractiveness ratings of pictures of men’s faces, men’s hands, and abstract art given by heterosexual women, before and after they saw genuine social information gathered in real time from their peers. Ratings of faces were influenced by social information, but no more or less than were images of hands and abstract art. Our results suggest that evidence for domain-specific social learning mechanisms in humans is weaker than previously suggested.
Molecular engineering of antibodies for site-specific covalent conjugation using CRISPR/Cas9
Authors: Khoshnejad Makan , Brenner Jacob S. , Motley William , Parhiz Hamideh , Greineder Colin F. , Villa Carlos H. , Marcos-Contreras Oscar A. , Tsourkas Andrew , Muzykantov Vladimir R.
Published: January 2018

Site-specific modification of antibodies has become a critical aspect in the development of next-generation immunoconjugates meeting criteria of clinically acceptable homogeneity, reproducibility, efficacy, ease of manufacturability, and cost-effectiveness. Using CRISPR/Cas9 genomic editing, we developed a simple and novel approach to produce site-specifically modified antibodies. A sortase tag was genetically incorporated into the C-terminal end of the third immunoglobulin heavy chain constant region (CH3) within a hybridoma cell line to manufacture antibodies capable of site-specific conjugation. This enabled an effective enzymatic site-controlled conjugation of fluorescent and radioactive cargoes to a genetically tagged mAb without impairment of antigen binding activity. After injection in mice, these immunoconjugates showed almost doubled specific targeting in the lung vs. chemically conjugated maternal mAb, and concomitant reduction in uptake in the liver and spleen. The approach outlined in this work provides a facile method for the development of more homogeneous, reproducible, effective, and scalable antibody conjugates for use as therapeutic and diagnostic tools.
Social rank-associated stress vulnerability predisposes individuals to cocaine attraction
Authors: Yanovich Chen , Kirby Michael L. , Michaelevski Izhak , Yadid Gal , Pinhasov Albert
Published: January 2018

Studies of personality have suggested that dissimilarities in ability to cope with stressful situations results in differing tendency to develop addictive behaviors. The present study used selectively bred stress-resilient, socially-dominant (Dom) and stress-vulnerable, socially-submissive (Sub) mice to investigate the interaction between environmental stress and inbred predisposition to develop addictive behavior to cocaine. In a Conditioned Place Preference (CPP) paradigm using cocaine, Sub mice displayed an aversion to drug, whereas Dom mice displayed drug attraction. Following a 4-week regimen of Chronic Mild Stress (CMS), Sub mice in CPP displayed a marked increase (>400%) in cocaine attraction, whereas Dom mice did not differ in attraction from their non-stressed state. Examination of hippocampal gene expression revealed in Sub mice, exposure to external stimuli, stress or cocaine, increased CRH expression (>100%), which was evoked in Dom mice only by cocaine exposure. Further, stress-induced decreases in DRD1 (>60%) and DRD2 (>50%) expression in Sub mice differed markedly from a complete lack of change in Dom mice. From our findings, we propose that social stratification dictates vulnerability to stress-induced attraction that may lead to addiction via differential regulation of hippocampal response to dopaminergic input, which in turn may influence differing tendency to develop addictive behaviors.
Reconstruction of cysteine biosynthesis using engineered cysteine-free enzymes
Authors: Fujishima Kosuke , Wang Kendrick M. , Palmer Jesse A. , Abe Nozomi , Nakahigashi Kenji , Endy Drew , Rothschild Lynn J.
Published: January 2018

Amino acid biosynthesis pathways observed in nature typically require enzymes that are made with the amino acids they produce. For example, Escherichia coli produces cysteine from serine via two enzymes that contain cysteine: serine acetyltransferase (CysE) and O-acetylserine sulfhydrylase (CysK/CysM). To solve this chicken-and-egg problem, we substituted alternate amino acids in CysE, CysK and CysM for cysteine and methionine, which are the only two sulfur-containing proteinogenic amino acids. Using a cysteine-dependent auxotrophic E. coli strain, CysE function was rescued by cysteine-free and methionine-deficient enzymes, and CysM function was rescued by cysteine-free enzymes. CysK function, however, was not rescued in either case. Enzymatic assays showed that the enzymes responsible for rescuing the function in CysE and CysM also retained their activities in vitro. Additionally, substitution of the two highly conserved methionines in CysM decreased but did not eliminate overall activity. Engineering amino acid biosynthetic enzymes to lack the so-produced amino acids can provide insights into, and perhaps eventually fully recapitulate via a synthetic approach, the biogenesis of biotic amino acids.
MRI of the cervical spinal cord predicts respiratory dysfunction in ALS
Authors: Grolez G. , Kyheng M. , Lopes R. , Moreau C. , Timmerman K. , Auger F. , Kuchcinski G. , Duhamel A. , Jissendi-Tchofo P. , Besson P. , Laloux C. , Petrault M. , Devedjian J. C. , Pérez Thierry , Pradat Pierre François , Defebvre L. , Bordet R. , Danel-Brunaud V. , Devos D.
Published: January 2018

For patients with amyotrophic lateral sclerosis (ALS), the primary therapeutic goal is to minimize morbidity. Non-invasive ventilation improves survival. We aim to assess whether Magnetic Resonance Imaging (MRI) of the cervical spinal cord predicts the progression of respiratory disorders in ALS. Brain and spinal MRI was repeatedly performed in the SOD1G86R mouse model, in 40 patients and in healthy controls. Atrophy, iron overload, white matter diffusivity and neuronal loss were assessed. In Superoxide Dismutase-1 (SOD1) mice, iron accumulation appeared in the cervical spinal cord at symptom onset but disappeared with disease progression (after the onset of atrophy). In ALS patients, the volumes of the motor cortex and the medulla oblongata were already abnormally low at the time of diagnosis. Baseline diffusivity in the internal capsule was predictive of functional handicap. The decrease in cervical spinal cord volume from diagnosis to 3 months was predictive of the change in slow vital capacity at 12 months. MRI revealed marked abnormalities at the time of ALS diagnosis. Early atrophy of the cervical spinal cord may predict the progression of respiratory disorders, and so may be of value in patient care and as a primary endpoint in pilot neuroprotection studies.
The functional and structural alterations of the striatum in chronic spontaneous urticaria
Authors: Wang Yuming , Fang Ji-Liang , Cui Bingnan , Liu Jiao , Song Ping , Lang Courtney , Bao Yan , Sun Ruirui , Xu Chenchen , Ding Xu , Yan Zhifang , Yan Yuhe , Kong Qian , Kong Jian
Published: January 2018

The brain has long been known to be the regulation center of itch, but the neuropathology of chronic itch, such as chronic spontaneous urticaria (CSU), remains unclear. Thus, we aimed to explore the brain areas involved in the pathophysiology of CSU in hopes that our results may provide valuable insights into the treatment of chronic itch conditions. 40 CSU patients and 40 healthy controls (HCs) were recruited. Urticaria activity scores 7 (UAS7) were collected to evaluate patient’s clinical symptoms. Amplitude of low frequency fluctuations (ALFF), voxel-based morphometry (VBM), and seed-based resting-state functional connectivity (rs-FC) analysis were used to assess brain activity and related plasticity. Compared with HCs, CSU patients exhibited 1) higher ALFF values in the right ventral striatum / putamen, which were positively associated with clinical symptoms as measured by UAS7; 2) gray matter volume (GMV) increase in the right ventral striatum and putamen; and 3) decreased rs-FC between the right ventral striatum and the right occipital cortex and between the right putamen and the left precentral gyrus. Using multiple-modality brain imaging tools, we demonstrated the dysfunction of the striatum in CSU. Our results may provide valuable insights into the neuropathology and development of chronic itch.
Optophysiological Characterisation of Inner Retina Responses with High-Resolution Optical Coherence Tomography
Authors: Erchova Irina , Tumlinson Alexandre R. , Fergusson James , White Nick , Drexler Wolfgang , Sengpiel Frank , Morgan James E.
Published: January 2018

Low coherence laser interferometry has revolutionised quantitative biomedical imaging of optically transparent structures at cellular resolutions. We report the first optical recording of neuronal excitation at cellular resolution in the inner retina by quantifying optically recorded stimulus-evoked responses from the retinal ganglion cell layer and comparing them with an electrophysiological standard. We imaged anaesthetised paralysed tree shrews, gated image acquisition, and used numerical filters to eliminate noise arising from retinal movements during respiratory and cardiac cycles. We observed increases in contrast variability in the retinal ganglion cell layer and nerve fibre layer with flash stimuli and gratings. Regions of interest were subdivided into three-dimensional patches (up to 5–15 μm in diameter) based on response similarity. We hypothesise that these patches correspond to individual cells, or segments of blood vessels within the inner retina. We observed a close correlation between the patch optical responses and mean electrical activity of the visual neurons in afferent pathway. While our data suggest that optical imaging of retinal activity is possible with high resolution OCT, the technical challenges are not trivial.
A facile synthesis of porous graphene for efficient water and wastewater treatment
Authors: Tabish Tanveer A. , Memon Fayyaz A. , Gomez Diego E. , Horsell David W. , Zhang Shaowei
Published: January 2018

The use of two-dimensional graphene-based materials in water treatment has recently gained significant attention due to their unique electronic and thermal mobility, high surface area, high mechanical strength, excellent corrosion resistance and tunable surface chemistry. However, the relatively expensive, poor hydrophobicity, low adsorption capacity and recyclability, and complex post-treatment of the most pristine graphene frameworks limit their practical application. Here, we report a facile scalable method to produce highly porous graphene from reduced graphene oxide via thermal treatment without addition of any catalyst or use of any template. Comparing to conventional graphene counterparts, as-prepared porous graphene nanosheets showed evident improvement in hydrophobicity, adsorption capacity, and recyclability, making them ideal candidate materials for water treatment. Superhydrophobic and superoleophilic porous graphene prepared in this work has been demonstrated as effective absorbents for a broad range of ions, oils and organic solvents, exhibiting high selectivity, good recyclability, and excellent absorption capacities > 90%. The synthesis method of porous graphene reported in this paper is easy to implement, low cost and scalable. These attributes could contribute towards efficient and cost-effective water purification and pollution reduction.
New Antimicrobial Potential and Structural Properties of PAFB: A Cationic, Cysteine-Rich Protein from Penicillium chrysogenum Q176
Authors: Huber Anna , Hajdu Dorottya , Bratschun-Khan Doris , Gáspári Zoltán , Varbanov Mihayl , Philippot Stéphanie , Fizil Ádám , Czajlik András , Kele Zoltán , Sonderegger Christoph , Galgóczy László , Bodor Andrea , Marx Florentine , Batta Gyula
Published: January 2018

Small, cysteine-rich and cationic proteins with antimicrobial activity are produced by diverse organisms of all kingdoms and represent promising molecules for drug development. The ancestor of all industrial penicillin producing strains, the ascomycete Penicillium chryosgenum Q176, secretes the extensively studied antifungal protein PAF. However, the genome of this strain harbours at least two more genes that code for other small, cysteine-rich and cationic proteins with potential antifungal activity. In this study, we characterized the pafB gene product that shows high similarity to PgAFP from P. chrysogenum R42C. Although abundant and timely regulated pafB gene transcripts were detected, we could not identify PAFB in the culture broth of P. chrysogenum Q176. Therefore, we applied a P. chrysogenum-based expression system to produce sufficient amounts of recombinant PAFB to address unanswered questions concerning the structure and antimicrobial function. Nuclear magnetic resonance (NMR)-based analyses revealed a compact β-folded structure, comprising five β-strands connected by four solvent exposed and flexible loops and an “abcabc” disulphide bond pattern. We identified PAFB as an inhibitor of growth of human pathogenic moulds and yeasts. Furthermore, we document for the first time an anti-viral activity for two members of the small, cysteine-rich and cationic protein group from ascomycetes.
Deep-sea hydrothermal vents as natural egg-case incubators at the Galapagos Rift
Authors: Salinas-de-León Pelayo , Phillips Brennan , Ebert David , Shivji Mahmood , Cerutti-Pereyra Florencia , Ruck Cassandra , Fisher Charles R. , Marsh Leigh
Published: January 2018

The discovery of deep-sea hydrothermal vents in 1977 challenged our views of ecosystem functioning and yet, the research conducted at these extreme and logistically challenging environments still continues to reveal unique biological processes. Here, we report for the first time, a unique behavior where the deep-sea skate, Bathyraja spinosissima, appears to be actively using the elevated temperature of a hydrothermal vent environment to naturally “incubate” developing egg-cases. We hypothesize that this behavior is directly targeted to accelerate embryo development time given that deep-sea skates have some of the longest egg incubation times reported for the animal kingdom. Similar egg incubating behavior, where eggs are incubated in volcanically heated nesting grounds, have been recorded in Cretaceous sauropod dinosaurs and the rare avian megapode. To our knowledge, this is the first time incubating behavior using a volcanic source is recorded for the marine environment.
Structural and functional characterization of shaft, anchor, and tip proteins of the Mfa1 fimbria from the periodontal pathogen Porphyromonas gingivalis
Authors: Hall Michael , Hasegawa Yoshiaki , Yoshimura Fuminobu , Persson Karina
Published: January 2018

Very little is known about how fimbriae of Bacteroidetes bacteria are assembled. To shed more light on this process, we solved the crystal structures of the shaft protein Mfa1, the regulatory protein Mfa2, and the tip protein Mfa3 from the periodontal pathogen Porphyromonas gingivalis. Together these build up part of the Mfa1 fimbria and represent three of the five proteins, Mfa1-5, encoded by the mfa1 gene cluster. Mfa1, Mfa2 and Mfa3 have the same overall fold i.e., two β-sandwich domains. Upon polymerization, the first β-strand of the shaft or tip protein is removed by indigenous proteases. Although the resulting void is expected to be filled by a donor-strand from another fimbrial protein, the mechanism by which it does so is still not established. In contrast, the first β-strand in Mfa2, the anchoring protein, is firmly attached by a disulphide bond and is not cleaved. Based on the structural information, we created multiple mutations in P. gingivalis and analysed their effect on fimbrial polymerization and assembly in vivo. Collectively, these data suggest an important role for the C-terminal tail of Mfa1, but not of Mfa3, affecting both polymerization and maturation of downstream fimbrial proteins.
Neural correlates underlying change in state self-esteem
Authors: Kawamichi Hiroaki , Sugawara Sho K. , Hamano Yuki H. , Kitada Ryo , Nakagawa Eri , Kochiyama Takanori , Sadato Norihiro
Published: January 2018

State self-esteem, the momentary feeling of self-worth, functions as a sociometer involved in maintenance of interpersonal relations. How others’ appraisal is subjectively interpreted to change state self-esteem is unknown, and the neural underpinnings of this process remain to be elucidated. We hypothesized that changes in state self-esteem are represented by the mentalizing network, which is modulated by interactions with regions involved in the subjective interpretation of others’ appraisal. To test this hypothesis, we conducted task-based and resting-state fMRI. Participants were repeatedly presented with their reputations, and then rated their pleasantness and reported their state self-esteem. To evaluate the individual sensitivity of the change in state self-esteem based on pleasantness (i.e., the subjective interpretation of reputation), we calculated evaluation sensitivity as the rate of change in state self-esteem per unit pleasantness. Evaluation sensitivity varied across participants, and was positively correlated with precuneus activity evoked by reputation rating. Resting-state fMRI revealed that evaluation sensitivity was positively correlated with functional connectivity of the precuneus with areas activated by negative reputation, but negatively correlated with areas activated by positive reputation. Thus, the precuneus, as the part of the mentalizing system, serves as a gateway for translating the subjective interpretation of reputation into state self-esteem.