bluuebunny/crossref_metadata_2025 huggingface dataset:
miRNAs, target genes expression and morphological analysis on the heart in gestational protein-restricted offspring
Authors: Gontijo José A.R. , Assalin Heloisa Balan , Boer Patrícia Aline
Published: December 2018

BACKGROUND

Gestational protein restriction was associated with low birth weight, hypertension and higher prevalence of cardiac disorders in adults. Several mechanisms, including epigenetics, could be related with the cardiovascular phenotype on protein-restricted offspring. Thus, we investigated the morphological cardiac effects of gestational protein restriction and left ventricle miRNAs and target genes expression pattern in both 12-day and 16-week old gestational protein-restricted male offspring.

METHODS

Pregnant Wistar rats were allocated into two groups, according to protein supply during pregnancy: NP (normal protein diet- 17%) or LP (low protein diet - 6%). The study evaluates the effects of maternal protein restriction on food consumption and body weight of both pregnant dams and offspring, systolic blood pressure in 16-wk old offspring and on cardiac morphometric and molecular parameters in both 12-d and 16-wk old offspring. RESULTS: Dams on the gestational protein-restricted diet had lower body weight gain and higher food intake. Gestational protein-restricted offspring had low birth weight, followed by rapidly body weight recovery, hypertension, and increased myocytes cross-sectional area and collagen fraction at 16-week old age. At 12-days old, miR-184, miR-192, miR-376c, miR-380-3p, miR-380-5p, miR-451, and miR-582-3p had increased expression, and miR-547 and miR-743a had decreased expression in the gestational protein-restricted left ventricle. At 16-week old, let-7b, miR-125a-3p, miR-142-3p, miR-182 and miR-188-5p had increased expression and let-7g, miR-107, miR-127, miR-181a, miR-181c, miR-184, miR-324-5p, miR-383, miR-423-5p and miR-484 had decreased expression in gestational protein-restricted left ventricle. Target predicted gene expression analysis shown higher expression of Dnmt3a, Oxct1, Rictor and Trps1 and lower expression of Bbs1 and Calml3 in 12-day old protein-restricted offspring. 16-week old protein-restricted offspring had higher expression of Adrbk1, Bbs1, Dnmt3a, Gpr22, Inppl1, and Oxct1 genes. CONCLUSION: Gestational protein restriction leads to offspring low birth weight, increased systolic blood pressure and morphological heart alterations that could be related to early heart miRNA expression changes that perpetuate into adulthood and which are associated with the regulation of essential genes involved in cardiovascular development, heart morphology, function, and metabolism.
Study of the binding mechanisms between palytoxin and its aptamer by docking and molecular simulation
Authors: Hu Bo , Zhou Rong , Li Zhengang , Qin Jiaxiang , Ouyang Shengqun , Li Zhen , Hu Wei , Wang Lianghua , Jiao Binghua
Published: December 2018

This paper provides a feasible model for aptamer and its target in molecular structure analysis and interaction mechanism. In this study, modeling and dynamic simulation of ssDNA aptamer (P-18S2) and target (Palytoxin,PTX) were performed separately. Then, the combination mechanism of DNA and PTX were predicted, and docking results showed that PTX can combine steadily in the groove at the top of DNA model trough strong hydrogen-bonds and electrostatic interaction. Therefore, we have further truncated and optimized to P-18S2 by simulating, at the same time, we also confirmed the reliability of simulative results by experimenting. Combining with the experimental and computational results, we provide a more reasonable interpretation for the high affinity and specific binding of P-18S2 and PTX and offer the basis for aptamer development in molecular diagnostics and therapeutic application.
Decrypting protein surfaces by combining evolution, geometry and molecular docking
Authors: Dequeker Chloé , Laine Elodie , Carbone Alessandra
Published: December 2018

The growing body of experimental and computational data describing how proteins interact with each other has emphasized the multiplicity of protein interactions and the complexity underlying protein surface usage and deformability. In this work, we propose new concepts and methods toward deciphering such complexity. We introduce the notion of interacting region to account for the multiple usage of a protein's surface residues by several partners and for the variability of protein interfaces coming from molecular flexibility. We predict interacting patches by crossing evolutionary, physico-chemical and geometrical properties of the protein surface with information coming from complete cross-docking (CC-D) simulations. We show that our predictions match well interacting regions and that the dierent sources of information are complementary. We further propose an indicator of whether a protein has a few or many partners. Our prediction strategies are implemented in the dynJET2 algorithm and assessed on a new dataset of 262 protein on which we performed CC-D. The code and the data are available at: http://www.lcqb.upmc.fr/dynJET2/.
A novel nonsense mutation c.424G>T (p. G142X) in the first exon of XLas leading to osteopetrosis
Authors: chen xiang , Meng Yang , Xie Ying , Wan Shan , Li Li , Zhang Jie , Su Bo , Yu Xijie
Published: December 2018

GNAS is one of the most complex gene loci in the human genome and encodes multiple gene products. XLas, the extra-large isoform of alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gas), is paternally inherited. Although XLas can mimic the action of Gas, its significance remains largely unknown in humans. Here we report a patient presented with increased bone mass, hypophosphatemia, and elevated parathyroid hormone levels. His serum calcium was in the lower limit of normal range. DEXA scan revealed progressive increase in the bone density of this patient. Whole exome sequencing of this subject found a novel nonsense mutation c.424G>T (p. G142X) in the first exon of XLas, which was inherited from his father and transmitted to his daughter. This mutation was predicted to exclusively influence the expression of XLas, while may have no significant effects on other gene products of this locus. SaOS2 cells transfected with mutant XLas failed to generate cAMP under parathyroid hormone stimulation, indicating skeletal resistance to this hormone. This subject showed higher circulating SOST, DKK1 and OPG levels, while lower RANKL levels and RANKL/OPG ratio, leading to reduced bone resorption. It is speculated that this patient may belong to a very rare type of pseudohypoparathyroidism with selective skeletal resistance but normal renal tubular response to parathyroid hormone. Our findings indicate that XLas plays a critical role in bone metabolism and GNAS locus should be considered as a candidate gene for high bone mass.
Antimicrobial activity of Mycobacteriophage D29 Lysin B during Mycobacterium ulcerans infection
Authors: Fraga Alexandra G. , Trigo Gabriela , Dominguez Juan , Silva-Gomes Rita , Gonçalves Carine M. , Oliveira Hugo , Castro António G. , Azeredo Joana , Pedrosa Jorge
Published: December 2018

Buruli Ulcer (BU) is a cutaneous disease caused by Mycobacterium ulcerans. The pathogenesis of BU is closely related to the secretion of the toxin mycolactone that induces extensive destruction of the skin and soft tissues. Although the World Health Organization recommends a combination of rifampicin and streptomycin for the treatment of BU, clinical management of advanced stages often requires extensive surgical resection of the infected tissue. Therefore, it is important to develop alternative strategies for the treatment of BU.
Endolysins (lysins) are phage encoded enzymes that degrade peptidoglycan of bacterial cell walls. Over the past years, lysins have been emerging as alternative antimicrobial agents against Gram-positive bacteria. Amongst Gram-positive bacteria, mycobacteria have an unusual outer membrane that is covalently attached to the mycolyl arabinogalactan-peptidoglycan complex. To overcome this additional barrier to phage-mediated lysis, some mycobacteriophages encode a lipolytic enzyme, Lysin B (Lys B).
In this study, we demonstrated for the first time that recombinant Lys B displays lytic activity against M. ulcerans isolates. Moreover, using a mouse model of M. ulcerans footpad infection, we show that subcutaneous treatment with Lys B leads to a reduction in bacterial burdens, associated with IFN-γ and TNF production in the draining lymph node. These findings highlight the potential use of lysins as a novel therapeutic approach against this neglected tropical disease.
The antiparasitic drug atovaquone inhibits arbovirus replication through the depletion of intracellular nucleotides.
Authors: Cifuentes Kottkamp Angelica , De Jesus Elfie , Grande Rebecca , Brown Julia K , Jacobs Adam R , Lim Jean K , Stapleford Kenneth
Published: December 2018

Arthropod-borne viruses represent a significant public health threat worldwide yet there are few antiviral therapies or prophylaxis targeting these pathogens. In particular, the development of novel antivirals for high-risk populations such as pregnant women is essential to prevent devastating disease such as that which was experienced with the recent outbreak of Zika virus (ZIKV) in the Americas. One potential avenue to identify new and pregnancy friendly antiviral compounds is to repurpose well-known and widely used FDA approved drugs. In this study, we addressed the antiviral role of atovaquone, a FDA Pregnancy Category C drug and pyrimidine biosynthesis inhibitor used for the prevention and treatment of parasitic infections. We found that atovaquone was able to inhibit ZIKV and chikungunya virus virion production in human cells and that this antiviral effect occurred early during infection at the initial steps of viral RNA replication. Moreover, we were able to complement viral replication and virion production with the addition of exogenous pyrimidine nucleosides indicating that atovaquone is functioning through the inhibition of the pyrimidine biosynthesis pathway to inhibit viral replication. Finally, using an ex vivo human placental tissue model, we found that atovaquone could limit ZIKV infection in a dose-dependent manner providing evidence that atovaquone may function as an antiviral in humans. Taken together, these studies suggest that atovaquone could be a broad-spectrum antiviral drug and a potential attractive candidate for the prophylaxis or treatment of arbovirus infection in vulnerable populations, such as pregnant women.
A Pivotal Role for Thiamine Deficiency in the Expression of Neuroinflammation Markers in Models of Alcohol‐Related Brain Damage
Authors: Toledo Nunes Polliana , Vedder Lindsey C. , Deak Terrence , Savage Lisa M.
Published: December 2018

Background

Alcohol‐related brain damage (ARBD) is associated with neurotoxic effects of heavy alcohol use and nutritional deficiency, in particular thiamine deficiency (TD), both of which induce inflammatory responses in brain. Although neuroinflammation is a critical factor in the induction of ARBD, few studies have addressed the specific contribution(s) of ethanol (EtOH) versus TD.

Methods

Adult rats were randomly divided into 6 conditions: chronic EtOH treatment (CET) where rats consumed a 20% v/v solution of EtOH for 6 months; CET with injections of thiamine (CET + T); severe pyrithiamine‐induced TD (PTD); moderate PTD; moderate PTD during CET; and pair‐fed controls. After the treatments, the rats were split into 3 recovery phase time points: the last day of treatment (time point 1), acute recovery (time point 2: 24 hours posttreatment), and delayed recovery (time point 3: 3 weeks posttreatment). At these time points, vulnerable brain regions (thalamus, hippocampus, frontal cortex) were collected and changes in neuroimmune markers were assessed using a combination of reverse transcription polymerase chain reaction and protein analysis.

Results

CET led to minor fluctuations in neuroimmune genes, regardless of the structure being examined. In contrast, PTD treatment led to a profound increase in neuroimmune genes and proteins within the thalamus. Cytokine changes in the thalamus ranged in magnitude from moderate (3‐fold and 4‐fold increase in interleukin‐1β [IL‐1β] and IκBα) to severe (8‐fold and 26‐fold increase in tumor necrosis factor‐α and IL‐6, respectively). Though a similar pattern was observed in the hippocampus and frontal cortex, overall fold increases were moderate relative to the thalamus. Importantly, neuroimmune gene induction varied significantly as a function of severity of TD, and most genes displayed a gradual recovery across time.

Conclusions

These data suggest an overt brain inflammatory response by TD and a subtle change by CET alone. Also, the prominent role of TD in the immune‐related signaling pathways leads to unique regional and temporal profiles of induction of neuroimmune genes.
Genetic Influences on the Amount of Cell Death in the Neural Tube of BXD Mice Exposed to Acute Ethanol at Midgestation
Authors: Théberge Emilie T. , Baker Jessica A. , Dubose Candis , Boyle Julia K. , Balce Kristina , Goldowitz Dan , Hamre Kristin M.
Published: December 2018

Background

Fetal alcohol spectrum disorders (FASD) have a strong genetic component although the genes that underlie this are only beginning to be elucidated. In the present study, one of the most common phenotypes of FASD, cell death within the early developing neural tube, was examined across a genetic reference population in a reverse genetics paradigm with the goal of identifying genetic loci that could influence ethanol (EtOH)‐induced apoptosis in the early developing neural tube.

Methods

BXD recombinant inbred mice as well as the parental strains were used to evaluate genetic differences in EtOH‐induced cell death after exposure on embryonic day 9.5. Dams were given either 5.8 g/kg EtOH or isocaloric maltose‐dextrin in 2 doses via intragastric gavage. Embryos were collected 7 hours after the initial exposure and cell death evaluated via TUNEL staining in the brainstem and forebrain. Genetic loci were evaluated using quantitative trait locus (QTL) analysis at GeneNetwork.org.

Results

Significant strain differences were observed in the levels of EtOH‐induced cell death that were due to genetic effects and not confounding variables such as differences in developmental maturity or cell death kinetics. Comparisons between the 2 regions of the developing neural tube showed little genetic correlation with the QTL maps exhibiting no overlap. Significant QTLs were found on murine mid‐chromosome 4 and mid‐chromosome 14 only in the brainstem. Within these chromosomal loci, a number of interesting candidate genes were identified that could mediate this differential sensitivity including Nfia (nuclear factor I/A) and Otx2 (orthodenticle homeobox 2).

Conclusions

These studies demonstrate that the levels of EtOH‐induced cell death occur in strain‐ and region‐dependent manners. Novel QTLs on mouse Chr4 and Chr14 were identified that modulate the differential sensitivity to EtOH‐induced apoptosis in the embryonic brainstem. The genes underlying these QTLs could identify novel molecular pathways that are critical in this phenotype.
Biomarker and Genomic Risk Factors for Liver Function Test Abnormality in Hazardous Drinkers
Authors: Whitfield John B. , Zhu Gu , Madden Pamela A. F. , Montgomery Grant W. , Heath Andrew C. , Martin Nicholas G.
Published: December 2018

Background

Alcohol dependence and long‐term excessive alcohol use may cause liver damage, but only some patients develop cirrhosis. Similarly, high alcohol intake without evident liver disease often but not always produces abnormal enzymatic liver function tests (LFTs), particularly gamma‐glutamyl transferase (GGT). We postulate that the factors predisposing to cirrhosis in alcoholics and to liver enzyme abnormality in drinkers are similar, and that biochemical LFTs could therefore be useful as markers of risk of alcoholic liver disease in excessive drinkers.

Methods

Data from participants in twin and twin‐family studies on alcohol use and dependence were used to identify 1,003 people who had reported excessive alcohol intake (28 drinks or more per week). A total of 962 of these provided blood for biochemical tests at the same time. Body mass index (BMI) and biomarkers of metabolic syndrome, inflammation, and iron stores were used in logistic regression with abnormality in serum GGT, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) as outcomes. We conducted genome‐wide association analyses for GGT, ALT, and AST separately in the group reporting excessive alcohol intake (N = 951) and a low‐intake group reporting 14 drinks or fewer per week (N = 8,716), and compared results.

Results

Abnormal GGT and ALT among excessive drinkers were associated with higher BMI, triglycerides, insulin, uric acid, C‐reactive protein, ferritin, and transferrin saturation; and with lower high‐density‐lipoprotein cholesterol. Abnormal AST was associated with triglycerides, ferritin, and transferrin saturation. ALT was significantly associated with variants at reported genetic loci for alcoholic liver disease (PNPLA3, rs738409, p = 0.0076; TM6SF2, rs10401969, p = 0.0076; HSD17B13, rs10433879, p = 0.0024).

Conclusions

Known risk factors for alcoholic cirrhosis including obesity and markers of metabolic syndrome, iron overload and inflammation are associated with liver enzyme abnormality in excessive drinkers.
Outcomes of induction of labour in nulliparous women at 38 to 39 weeks pregnancy by clinical indication: An observational study
Authors: de Vries Bradley Stephen , Barratt Alexandra , McGeechan Kevin , Tooher Jane , Wong Ebony , Phipps Hala , Gordon Adrienne , Hyett Jon Anthony
Published: December 2018

Background

Knowledge of the outcomes of induction of labour for different indications is sparse.

Aims

To describe the mode of birth and other outcomes for nulliparous women induced at 38–39 weeks gestational age by indication for induction of labour.

Material and methods

This was a retrospective observational study in a tertiary referral hospital, and a metropolitan teaching hospital in Sydney. The study population was nulliparous women with induction of labour at 38 or 39 completed weeks of pregnancy and a singleton, cephalic presenting baby planning a vaginal birth, from 2009 to 2016. The indication for induction of labour was classified into 12 groups. Mode of birth and other maternal and perinatal outcomes were described in each group, for women who spontaneously laboured at 38 or 39 weeks, and for women who gave birth from 40 completed weeks onward. The main outcome measure was mode of birth.

Results

There were 3330 women with induction of labour at 38 or 39 weeks gestation. Rates of vaginal birth varied widely, ranging from 54% when the indication for induction was suspected large fetus, to 82% when the indication was suspected fetal compromise, and was 74% overall. Indications for caesarean delivery also varied by indication for induction. Among women giving birth ≥40 weeks gestational age, 75% had a vaginal birth.

Conclusions

In nulliparous women, rates of vaginal birth following induction of labour at 38 or 39 weeks gestation vary widely according to the indication for induction. These data are useful for antenatal counselling.
Immunotherapy with grass pollen tablets reduces medication dispensing for allergic rhinitis and asthma: A retrospective database study in France
Authors: Devillier Philippe , Molimard Mathieu , Ansolabehere Xavier , Bardoulat Isabelle , Coulombel Nicolas , Maurel Frédérique , Le Jeunne Philippe , Demoly Pascal
Published: December 2018

Background

Moderate‐to‐severe allergic rhinitis (AR) may increase the risk of developing or worsening asthma, whereas treatment of AR with subcutaneously or sublingual allergen immunotherapy (SLIT) may slow this progression.

Methods

In a retrospective real‐world analysis, prescription fulfilment data were gathered from French retail pharmacies between 1 March 2012 and 31 December 2016. Using linear regression analyses, patients having received at least two prescriptions of grass pollen SLIT tablets over at least 2 successive years were compared with control patients having received symptomatic medications only.

Results

A total of 1099 SLIT patients and 27 475 control patients were included in the main analysis. With regard to symptomatic AR medication dispensing, we observed a 50% decrease in the pre‐index/follow‐up ratio in the SLIT group, a 30% increase in the control group without age matching (P < 0.0001 vs SLIT) and a 20% increase in the control group with age matching (P < 0.0001 vs SLIT). During the follow‐up, 11 (1.8%) and 782 (5.3%) patients initiated asthma treatment in the SLIT and control groups, respectively. The relative risk of medication dispensing for new asthma was lower in the SLIT group (by 62.5% [29.1%‐80.1%] without age matching (P = 0.0025) and by 63.7% [31.5%‐80.7%] with age matching; P = 0.0018). SLIT was also associated with slower progression of asthma medication dispensing during the follow‐up period, relative to the control group (regression coefficient: −0.58 [−0.74 to 0.42] without age matching (P < 0.0001) and −0.61 [−0.76 to −0.46] with age matching; P < 0.0001).

Conclusion

Prescription of grass pollen SLIT tablets reduced the dispensing of AR and asthma medications in real life.
Inverted U‐shaped relationship between vitamin D and ever‐reported eczema in US adults
Authors: Wei Jia , Jaleel Tarannum , MacLeod Amanda S. , Ji John S.
Published: December 2018

Background

Eczema is a skin condition which affects up to 10% to 20% of people worldwide. Previous literature finds that low vitamin D levels may be a risk factor for eczema, but the association is not clear.

Methods

We used the cross‐sectional data from U.S. National Health and Nutrition Examination Survey 2005‐2006. Adults were defined as 20 years and older. The association between eczema and serum 25‐hydroxyvitamin D [25(OH)D] was estimated using multivariate logistic regression models adjusted for patient demographics, lifestyle variables, stress, and medical comorbidities. Restricted cubic spline analyses were performed to explore nonlinear relationship. We also stratified by race.

Results

A total of 3921 adults were included in the analysis. The prevalence of ever‐report of eczema was 7.94% in US adults. Reports of eczema were higher in people with higher socioeconomic status, depressive symptoms, previous history of asthma and hay fever, female, sampled in summer, and nonHispanic white. The logistic regression found higher odds ratio of eczema in vitamin D deficiency group (<50 nmol/L) compared to sufficiency group (>75 nmol/L) (OR = 1.81, 95% CI: 1.09‐3.01, P = 0.02). The spline analysis found an inverted U‐shaped relationship between eczema and serum 25(OH)D level. Eczema risk reached the highest at around 45 nmol/L, with decreasing risk in both directions away from this value. This relationship was absent in nonHispanic black population.

Conclusion

Vitamin D is associated with reports of eczema in nonHispanic white population, but not in the nonHispanic black population in the United States.
Bacterial secretion of histamine within the gut influences immune responses within the lung
Authors: Barcik Weronika , Pugin Benoit , Brescó Marina Sabaté , Westermann Patrick , Rinaldi Arturo , Groeger David , Van Elst Dries , Sokolowska Milena , Krawczyk Krzysztof , Frei Remo , Ferstl Ruth , Wawrzyniak Marcin , Altunbulakli Can , Akdis Cezmi A. , O'Mahony Liam
Published: December 2018

Background

Histamine is an important immunomodulator influencing both the innate and adaptive immune system. Certain host cells express the histidine decarboxylase enzyme (HDC), which is responsible for catalysing the decarboxylation of histidine to histamine. We and others have shown that bacterial strains can also express HDC and secrete histamine; however, the influence of bacterial‐derived histamine on the host immune responses distant to the gut is unclear.

Methods

The Escherichia coli BL21 (E coli BL21) strain was genetically modified to express the Morganella morganii (M morganii)‐derived HDC gene (E coli BL21_HTW). E coli BL21 and E coli BL21_HTW were gavaged to ovalbumin (OVA) sensitized and challenged mice to investigate the effect of bacterial‐derived histamine on lung inflammatory responses.

Results

Oral administration of E coli BL21_HTW, which is able to secrete histamine, to wild‐type mice reduced lung eosinophilia and suppressed ex vivo OVA‐stimulated cytokine secretion from lung cells in the OVA respiratory inflammation mouse model. In histamine receptor 2 (H2R)‐deficient mice, administration of histamine‐secreting bacteria also reduced inflammatory cell numbers in bronchoalveolar lavage (BAL). However, the suppressive effect of bacterial‐derived histamine on BAL inflammation was lost in HDC‐deficient mice. This loss of activity was associated with increased expression of histamine degrading enzymes and reduced histamine receptor expression.

Conclusion

Histamine secretion from bacteria within the gut can have immunological consequences at distant mucosal sites, such as within the lung. These effects are influenced by host histamine receptor expression and the expression of histamine degrading enzymes.
Systematic review and meta‐analysis of the association between childhood physical activity and age at menarche
Authors: Calthorpe Lucia , Brage Soren , Ong Ken K.
Published: December 2018

Aim

To systematically appraise and summarise published evidence on the association between childhood physical activity (PA) and subsequent age at menarche (AAM).

Methods

We searched PubMed (1990–2018) for studies that reported the relationship between childhood PA and AAM. We performed tabular synthesis of population‐based studies and a random‐effects meta‐analysis of results of athlete/nonathlete studies.

Results

One randomised controlled trial was identified, in which an intervention to prevent obesity reduced the likelihood of menarche during the two‐year study period (relative risk: 0.75, 95% CI: 0.66–0.87; n = 422 girls). One of five prospective cohort studies (total n = 4492) reported a significant association between self‐reported PA duration and subsequent menarche timing. Four of five historical cohort studies (total n = 89 470) reported significant associations between recalled premenarcheal PA and later AAM. Meta‐analysis across 12 athlete/nonathlete studies showed that menarche occurred 1.13 years later (95% CI: 0.80–1.47) in athletes compared to nonathletes.

Conclusion

These findings suggest that AAM is a behaviourally modifiable trait. However, the quality of reported population‐based study evidence is low and estimation of the true relationship between childhood PA and AAM is likely confounded by concomitant changes in diet and lifestyle behaviours.
Cardiotrophin‐1 opposes renal fibrosis in mice: Potential prevention of chronic kidney disease
Authors: Perretta‐Tejedor Nuria , Muñoz‐Félix José M. , Düwel Annette , Quiros‐Luis Yaremi , Fernández‐Martín José L. , Morales Ana I. , López‐Hernández Francisco J. , López‐Novoa José M. , Martínez‐Salgado Carlos
Published: December 2018

Aim

Chronic kidney disease is characterized by tubulointerstitial fibrosis involving inflammation, tubular apoptosis, fibroblast proliferation and extracellular matrix accumulation. Cardiotrophin‐1, a member of the interleukin‐6 family of cytokines, protects several organs from damage by promoting survival and anti‐inflammatory effects. However, whether cardiotrophin‐1 participates in the response to chronic kidney injury leading to renal fibrosis is unknown.

Methods

We hypothesized and assessed the potential role of cardiotrophin‐1 in a mice model of tubulointerstitial fibrosis induced by unilateral ureteral obstruction (UUO).

Results

Three days after UUO, obstructed kidneys from cardiotrophin‐1−/− mice show higher expression of inflammatory markers IL‐1β, Cd68, ICAM‐1, COX‐2 and iNOs, higher activation of NF‐κB, higher amount of myofibroblasts and higher severity of tubular damage and apoptosis, compared with obstructed kidneys from wild‐type littermates. In a later stage, obstructed kidneys from cardiotrophin‐1−/− mice show higher fibrosis than obstructed kidneys from wild‐type mice. Interestingly, administration of exogenous cardiotrophin‐1 prevents the increased fibrosis resulting from the genetic knockout of cardiotrophin‐1 upon UUO, and supplementation of wild‐type mice with exogenous cardiotrophin‐1 further reduces the renal fibrosis induced by UUO. In vitro, renal myofibroblasts from cardiotrophin‐1−/− mice have higher collagen I and fibronectin expression and higher NF‐κB activation than wild‐type cells.

Conclusions

Cardiotrophin‐1 participates in the endogenous response that opposes renal damage by counteracting the inflammatory, apoptotic and fibrotic processes. And exogenous cardiotrophin‐1 is proposed as a candidate for the treatment and prevention of chronic renal fibrosis.
Letter: reduction in projected mortality or need for liver transplantation associated with bezafibrate add‐on in primary biliary cholangitis with incomplete UDCA response
Authors: Corpechot Christophe , Chazouillères Olivier , Lemoinne Sara , Rousseau Alexandra
Published: December 2018

Linked Content

This article is linked to Jones and Hansen, Cheung et al and Cheung et al papers. To view these articles, visit https://doi.org/10.1111/apt.13507, https://doi.org/10.1111/apt.13519 and https://doi.org/10.1111/apt.13465.
Editorial: predicting response to treatment in children with Crohn's disease
Authors: Lemberg Daniel A. , Day Andrew S.
Published: December 2018

Linked Content

This article is linked to Ziv‐Baran et al paper. To view this article,
visit https://doi.org/10.1111/apt.15016.
Letter: SPOSIB SB2—a Sicilian prospective observational study of IBD patients treated with infliximab biosimilar SB2
Authors: Macaluso Fabio Salvatore , Cappello Maria , Giuffrida Enrica , Fries Walter , Centritto Andrea , Privitera Antonio Carlo , Inserra Gaetano , Vassallo Roberto , Magnano Antonio , Vinci Elisa , Garufi Serena , Ventimiglia Marco , Renna Sara , Orlando Rosalba , Rizzuto Giulia , Cottone Mario , Orlando Ambrogio ,   Sicilian Network for Inflammatory Bowel Disease (SN‐IBD)
Published: December 2018

Linked Content

This article is linked to Schmitz et al paper. To view these articles, visit https://doi.org/10.1111/apt.14453.
Condition mimicking peritoneal metastasis associated with preoperative staging laparoscopy in advanced gastric cancer
Authors: Ushimaru Yuki , Fujiwara Yoshiyuki , Shishido Yuji , Omori Takeshi , Yanagimoto Yoshitomo , Sugimura Keijirou , Moon Jeong‐Ho , Miyata Hiroshi , Yano Masahiko
Published: December 2018

Preoperative staging laparoscopy is used to search for peritoneal dissemination or distant metastasis as part of the treatment strategy for advanced gastric cancer. We observed pseudo‐peritoneal metastasis during laparotomy in 6 of 49 patients in whom lack of peritoneal dissemination had been confirmed by preoperative staging laparoscopy. In all cases, suspected nodules were biopsied and subjected to rapid histological diagnosis. However, a definite malignant or benign diagnosis could not be obtained via a rapid histological examination during surgery. A final histological examination combined with immunohistological analysis using formalin‐fixed embedded tissues confirmed no malignancy after surgery in all cases. These rapidly growing nodules that mimic peritoneal metastasis are thought to be associated with the use of grasping forceps during staging laparoscopy. No cases have been reported in which peritoneal nodules mimicking peritoneal metastasis occurred after staging laparoscopy, and surgeons should consider this possibility in patients treated shortly after staging laparoscopy.
Pharmacogenomics research and clinical implementation in Brazil
Authors: Rodrigues‐Soares Fernanda , Suarez‐Kurtz Guilherme
Published: December 2018

We searched PubMed entries and the Lattes database of Brazilian Pharmacogenetics Network investigators, for pharmacogenetic/genomic (PGx) studies in the Brazilian population, focusing on the drugs and genes included in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Warfarin was the most extensively studied drug in a PGx context: a genomewide association study targeting warfarin stable dose identified significant signals in VKORC1 and CYP2C9, several PGx dosing algorithms were developed based on these and other genes, and the implications of population admixture on extrapolation of dosing recommendations in the CPIC guidelines were examined. A study in renal transplanted patients disclosed association of CYP3A5*6 and CYP3A5*7 with tacrolimus dosing, which led to addition of these variants to CYP3A5*3 in the CPIC tacrolimus guideline. Studies verified predisposition of HIV‐positive carriers of UGT1A1*28 to severe atazanavir‐induced hyperbilirubinaemia, intolerance to 5‐fluorouracyl in gastrointestinal cancer patients with deleterious DPYD variants, failure of HCV‐infected carriers of IFNL3 rs12979860 to obtain a sustained viral response to PEG‐IFN‐α, and hypersensitivity reactions to abacavir in HIV‐positive carriers of HLA‐B*57:01. No prospective analyses of drug therapy outcomes or cost‐effectiveness assessments of PGx‐guided therapy were found. In conclusion, the limited adoption of PGx‐informed drug prescription in Brazil reflects combination of recognized barriers to PGx implementation worldwide plus factors specific to the Brazilian population. The latter include rarity/absence of genetic variants on which international PGx guidelines are based (eg HLA‐B*15.02 for phenytoin and carbamazepine) and the caveat of extrapolating to the admixed Brazilian population, guidelines based on categorical variables, such as continental ancestry (eg warfarin guidelines), “race” or ethnicity.
Is Job Insecurity Higher in Leveraged Buyouts?
Authors: Bacon Nick , Hoque Kim , Wright Mike
Published: December 2018

This article assesses whether job insecurity is higher in leveraged buyouts (LBOs) than elsewhere. It draws on matched employer‐employee data from the British 2011 Workplace Employment Relations Study linked to data from the Centre for Management Buyout Research. The analysis finds no consistent evidence of higher job insecurity in LBOs as measured by workforce reduction practices (redundancy rates, job security/no‐compulsory redundancies policies and redundancy consultation), dismissal rates, labour use practices (non‐permanent employment contracts and outsourcing) and employees’ job security perceptions. Job insecurity is no higher in either current or former LBOs than elsewhere. Contrary to what might be expected, it is also no higher in private equity (PE)‐backed LBOs, management buy‐ins or high‐debt LBOs and there is only partial and weak evidence of higher job insecurity in short‐hold LBOs. Job insecurity is also no higher in perfect storm LBOs (PE‐backed management buy‐ins that are short‐holds with high‐debt). Concerns over the negative implications of LBOs for job security thus appear misplaced.
Recent advances in the histo‐molecular pathology of human prion disease
Authors: Baiardi Simone , Rossi Marcello , Capellari Sabina , Parchi Piero
Published: December 2018

Prion diseases are progressive neurodegenerative disorders affecting humans and other mammalian species. The term prion, originally put forward to propose the concept that a protein could be infectious, refers to PrPSc, a misfolded isoform of the cellular prion protein (PrPC) that represents the pathogenetic hallmark of these disorders. The discovery that other proteins characterized by misfolding and seeded aggregation can spread from cell to cell, similarly to PrPSc, has increased interest in prion diseases. Among neurodegenerative disorders, however, prion diseases distinguish themselves for the broader phenotypic spectrum, the fastest disease progression and the existence of infectious forms that can be transmitted through the exposure to diseased tissues via ingestion, injection or transplantation. The main clinicopathological phenotypes of human prion disease include Creutzfeldt–Jakob disease, by far the most common, fatal insomnia, variably protease‐sensitive prionopathy, and Gerstmann–Sträussler–Scheinker disease. However, clinicopathological manifestations extend even beyond those predicted by this classification. Because of their transmissibility, the phenotypic diversity of prion diseases can also be propagated into syngenic hosts as prion strains with distinct characteristics, such as incubation period, pattern of PrPSc distribution and regional severity of histopathological changes in the brain. Increasing evidence indicates that different PrPSc conformers, forming distinct ordered aggregates, encipher the phenotypic variants related to prion strains. In this review, we summarize the most recent advances concerning the histo‐molecular pathology of human prion disease focusing on the phenotypic spectrum of the disease including co‐pathologies, the characterization of prion strains by experimental transmission and their correlation with the physicochemical properties of PrPSc aggregates.
A novel nitroalkene‐α‐tocopherol analogue inhibits inflammation and ameliorates atherosclerosis in Apo E knockout mice
Authors: Rodriguez‐Duarte Jorge , Galliussi Germán , Dapueto Rosina , Rossello Jessica , Malacrida Leonel , Kamaid Andrés , Schopfer Francisco J , Escande Carlos , López Gloria V , Batthyány Carlos
Published: December 2018

Background and purpose

Atherosclerosis is characterized by chronic low‐grade inflammation with concomitant lipid accumulation in the arterial wall. Anti‐inflammatory and anti‐atherogenic properties have been described for a novel class of endogenous nitroalkenes (nitrated‐unsaturated fatty acids), formed during inflammation and digestion/absorption processes. The lipid‐associated antioxidant α‐tocopherol is transported systemically by LDL particles including to the atheroma lesions. To capitalize on the overlapping and complementary salutary properties of endogenous nitroalkenes and α‐tocopherol, we designed and synthesized a novel nitroalkene‐α‐tocopherol analogue (NATOH) to address chronic inflammation and atherosclerosis, particularly at the lesion sites.

Experimental approach

We synthesized NATOH, determined its electrophilicity and antioxidant capacity and studied its effects over pro‐inflammatory and cytoprotective pathways in macrophages in vitro. Moreover, we demonstrated its incorporation into lipoproteins and tissue both in vitro and in vivo, and determined its effect on atherosclerosis and inflammatory responses in vivo using the Apo E knockout mice model.

Key results

NATOH exhibited similar antioxidant capacity to α‐tocopherol and, due to the presence of the nitroalkenyl group, like endogenous nitroalkenes, it exerted electrophilic reactivity. NATOH was incorporated in vivo into the VLDL/LDL lipoproteins particles to reach the atheroma lesions. Furthermore, oral administration of NATOH down‐regulated NF‐κB‐dependent expression of pro‐inflammatory markers (including IL‐1β and adhesion molecules) and ameliorated atherosclerosis in Apo E knockout mice.

Conclusions and implications

In toto, the data demonstrate a novel pharmacological strategy for the prevention of atherosclerosis based on a creative, natural and safe drug delivery system of a non‐conventional anti‐inflammatory compound (NATOH) with significant potential for clinical application.
Stimulation of histamine H4 receptors increases the production of IL‐9 in Th9 polarized cells
Authors: Schaper‐Gerhardt Katrin , Wohlert Mareike , Mommert Susanne , Kietzmann Manfred , Werfel Thomas , Gutzmer Ralf
Published: December 2018

Background and Purpose

Th9 cells represent a recently defined subset of CD4+ T‐helper cells, characterized by a high production of IL‐9. They are found at increased frequency in lesions of atopic dermatitis, where IL‐9 is also elevated. As histamine is up‐regulated in lesions of inflammatory skin diseases, we investigated the expression profile of histamine receptors and their functional role on Th9 cells.

Experimental Approach

Naïve CD4+ T‐cells were purified from human peripheral blood mononuclear cells, using magnetic beads and further differentiated into Th9 cells. During differentiation, cells were additionally stimulated with histamine receptor agonists or left untreated. Histamine receptor expression as well as IL‐9 production was measured.

Key Results

As proof of a successful differentiation, IL‐9 production was measured at mRNA and protein level. Expression of mRNA for histamine H1, H2 and H4 receptors were up‐regulated in differentiated Th9 cells compared to Th0 cells, while no mRNA for the H3 receptor was detectable. Stimulation of Th9 cells with histamine significantly up‐regulated expression of mRNA and protein for IL‐9 . Experiments with specific histamine receptor agonists and antagonists revealed that this up‐regulation was mediated by H4 receptors.

Conclusions and Implications

In summary, our study demonstrates a functional role for histamine H4 receptors on Th9 cells, which might amplify the pro‐inflammatory potency of these cells. Together with earlier studies on Th2 and Th17 cells, this study underlines the promising approach for the use of H4 receptor antagonists in inflammatory and allergic diseases such as atopic dermatitis.

Linked Articles

This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc
Assessing the fitness consequences of mitonuclear interactions in natural populations
Authors: Hill Geoffrey E. , Havird Justin C. , Sloan Daniel B. , Burton Ronald S. , Greening Chris , Dowling Damian K.
Published: December 2018

Metazoans exist only with a continuous and rich supply of chemical energy from oxidative phosphorylation in mitochondria. The oxidative phosphorylation machinery that mediates energy conservation is encoded by both mitochondrial and nuclear genes, and hence the products of these two genomes must interact closely to achieve coordinated function of core respiratory processes. It follows that selection for efficient respiration will lead to selection for compatible combinations of mitochondrial and nuclear genotypes, and this should facilitate coadaptation between mitochondrial and nuclear genomes (mitonuclear coadaptation). Herein, we outline the modes by which mitochondrial and nuclear genomes may coevolve within natural populations, and we discuss the implications of mitonuclear coadaptation for diverse fields of study in the biological sciences. We identify five themes in the study of mitonuclear interactions that provide a roadmap for both ecological and biomedical studies seeking to measure the contribution of intergenomic coadaptation to the evolution of natural populations. We also explore the wider implications of the fitness consequences of mitonuclear interactions, focusing on central debates within the fields of ecology and biomedicine.
Phosphorylation status at Smad3 linker region modulates transforming growth factor‐β‐induced epithelial‐mesenchymal transition and cancer progression
Authors: Ooshima Akira , Park Jinah , Kim Seong‐Jin
Published: December 2018

Smad3, a major transcription factor in transforming growth factor‐β (TGF‐β) signaling, plays critical roles in both tumor‐suppressive and pro‐oncogenic functions. Upon TGF‐β stimulation, the C‐terminal tail of Smad3 undergoes phosphorylation that is essential for canonical TGF‐β signaling. The Smad3 linker region contains serine/threonine phosphorylation sites and can be phosphorylated by intracellular kinases, such as the MAPK family, cyclin‐dependent kinase (CDK) family and glycogen synthase kinase‐3β (GSK‐3β). Previous reports based on cell culture studies by us and others showed that mutation of Smad3 linker phosphorylation sites dramatically intensifies TGF‐β responses as well as growth‐inhibitory function and epithelial‐mesenchymal transition (EMT), suggesting that Smad3 linker phosphorylation suppresses TGF‐β transcriptional activities. However, recent discoveries of Smad3‐interacting molecules that preferentially bind phosphorylated Smad3 linker serine/threonine residues have shown a multitude of signal transductions that either enhance or suppress TGF‐β responses associated with Smad3 turnover or cancer progression. This review aims at providing new insight into the perplexing mechanisms of TGF‐β signaling affected by Smad3 linker phosphorylation and further attempts to gain insight into elimination and protection of TGF‐β‐mediated oncogenic and growth‐suppressive signals, respectively.
Phase I study of alpelisib (BYL719), an α‐specific PI3K inhibitor, in Japanese patients with advanced solid tumors
Authors: Ando Yuichi , Iwasa Satoru , Takahashi Shunji , Saka Hideo , Kakizume Tomoyuki , Natsume Kazuto , Suenaga Naoko , Quadt Cornelia , Yamada Yasuhide
Published: December 2018

This phase I study aimed to determine tolerability and preliminary efficacy of single‐agent alpelisib (BYL719) in Japanese patients with advanced solid malignancies. The primary objective of the study was to estimate the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of oral alpelisib in patients with advanced solid tumors who had progressed despite standard therapy. The expansion part included patients with PIK3CA mutation/amplification; safety, preliminary efficacy, pharmacokinetic (PK)/pharmacodynamic profile, and food effect on the PK profile of alpelisib at the MTD/RP2D were determined. Oral alpelisib was given as a single agent on a continuous 28‐day treatment cycle once daily. Overall, 33 patients received alpelisib. Dose‐limiting toxicities were observed in 2 patients in the escalation part (at 400 mg/day) and 1 patient in the expansion part (at 350 mg/day). The RP2D of alpelisib was determined as 350 mg/day based on overall safety profile in the dose escalation part and previous data from a Western population; the MTD was not determined. The most common all‐grade treatment‐suspected adverse events were hyperglycemia and maculopapular rash (48.5% each) and diarrhea (45.5%). The PK of alpelisib in the Japanese population was similar to that reported in the Western population. The overall response rate, disease control rate, and median progression‐free survival at 350 mg/day were 3%, 57.6%, and 3.4 months, respectively. Alpelisib as single agent showed a favorable safety profile and encouraging preliminary efficacy in Japanese patients with advanced solid tumors.
JARID1B expression and its function in DNA damage repair are tightly regulated by miRNAs in breast cancer
Authors: Mocavini Ivano , Pippa Simone , Licursi Valerio , Paci Paola , Trisciuoglio Daniela , Mannironi Cecilia , Presutti Carlo , Negri Rodolfo
Published: December 2018

JARID1B/KDM5B histone demethylase's mRNA is markedly overexpressed in breast cancer tissues and cell lines and the protein has been shown to have a prominent role in cancer cell proliferation and DNA repair. However, the mechanism of its post‐transcriptional regulation in cancer cells remains elusive. We performed a computational analysis of transcriptomic data from a set of 103 breast cancer patients, which, along with JARID1B upregulation, showed a strong downregulation of 2 microRNAs (miRNAs), mir‐381 and mir‐486, potentially targeting its mRNA. We showed that both miRNAs can target JARID1B 3′UTR and reduce luciferase's activity in a complementarity‐driven repression assay. Moreover, MCF7 breast cancer cells overexpressing JARID1B showed a strong protein reduction when transfected with mir‐486. This protein's decrease is accompanied by accumulation of DNA damage, enhanced radiosensitivity and increase of BRCA1 mRNA, 3 features previously correlated with JARID1B silencing. These results enlighten an important role of a miRNA’s circuit in regulating JARID1B's activity and suggest new perspectives for epigenetic therapies.