bluuebunny/crossref_metadata_2025 huggingface dataset:
Single Index Methods for Evaluation of Marker-guided Treatment Rules Based on Multivariate Marker Panels
Authors: Skrivankova Veronika , Heagerty Patrick J.
Published: August 2017

Clinical practice may be enhanced by use of person-level information that could guide treatment choice and lead to better outcomes for both treated individuals and for the population. The scientific challenge is to identify and validate those factors that can reliably be used to target treatment, and to accurately quantify the expected treatment benefit as a function of candidate markers. Our proposal is to explicitly focus on smooth non-parametric evaluation of a canonical single index score that estimates the expected treatment benefit associated with patient characteristics. Our methods intentionally decouple the model used to generate the treatment benefit score from the methods that are adopted to evaluate the performance of the resulting single index score. We are motivated by the practical issue that model performance can not realistically be evaluated for every specific covariate value due to intrinsic sparseness. However, direct validation of a scalar treatment benefit score obtained through model-based dimension reduction is feasible, and we believe should be the focus of validation efforts. We also show that the canonical single index treatment benefit score can be used for selecting subsets of patients with enriched expected treatment response since patients can be easily ordered and grouped based on the scalar score. Our biomedical motivation comes from a recent randomized trial of steroid injections for low back pain where baseline clinical and imaging data are candidate measures for guiding therapeutic choice.
Microtubule actin cross‐linking factor 1, a novel potential target in cancer
Authors: Miao Zhiping , Ali Arshad , Hu Lifang , Zhao Fan , Yin Chong , Chen Chu , Yang Tuanmin , Qian Airong
Published: August 2017

Cancer is a polygenic disease characterized by uncontrolled growth of normal body cells, deregulation of the cell cycle as well as resistance to apoptosis. The spectraplakin protein microtubule actin cross‐linking factor 1 (MACF1) plays an essential function in various cellular processes, including cell proliferation, migration, signaling transduction and embryo development. MACF1 is also involved in processes such as metastatic invasion in which cytoskeleton organization is a critical element that contributes to tumor progression in various human cancers. Aberrant expression of MACF1 initiates the tumor cell proliferation, and migration and metastasis in numerous cancers, such as breast cancer, colon cancer, lung cancer and glioblastoma. In this review, we summarized the current knowledge of MACF1 and its critical role in different human cancers. This will be helpful for researchers to investigate the novel functional role of MACF1 in human cancers and as a potential target to enhance the efficacy of therapeutic treatment modalities.
Metformin enhances doxorubicin sensitivity via inhibition of doxorubicin efflux in P‐gp‐overexpressing MCF‐7 cells
Authors: Shafiei‐Irannejad Vahid , Samadi Nasser , Yousefi Bahman , Salehi Roya , Velaei Kobra , Zarghami Nosratollah
Published: August 2017

Resistance against chemotherapy is still a major problem in successful cancer treatment in the clinic. Therefore, identifying new compounds with lower side‐effects and higher efficacy is an important approach to overcome multidrug resistance (MDR). Here, we investigated the activity and possible mechanism of the antidiabetic drug, metformin, in human doxorubicin (DOX)‐resistant breast cancer (MCF‐7/DOX) cells. The effect of metformin on the cytotoxicity of DOX was evaluated by MTT assay. The P‐gp mRNA/protein expression levels following treatment with metformin were determined using real‐time polymerase chain reaction and Western blot analysis, respectively. Intracellular rhodamine 123 accumulation assay was performed to evaluate the P‐gp function. Cellular ATP content was determined using ATP assay kit. The effect of metformin on DOX‐induced apoptosis was evaluated by annexin V/FITC assay. Exposure to metformin considerably enhanced the cytotoxicity of DOX. Metformin had no substantial effect on P‐gp expression, while the activity of P‐gp and intracellular ATP content decreased with metformin treatment in a dose‐dependent manner. Furthermore, metformin significantly increased the DOX‐induced apoptosis. These results indicate that metformin could reverse MDR in breast cancer cells by reducing P‐gp activity. Therefore, metformin can be suggested as a potent adjuvant in breast cancer chemotherapy.
Prevalence of treated hypothyroidism in the community: Analysis from general practices in North‐East England with implications for the United Kingdom
Authors: Ingoe Lorna , Phipps Norah , Armstrong Gary , Rajagopal Arvind , Kamali Farzan , Razvi Salman
Published: August 2017

Objective

Hypothyroidism is more frequently diagnosed in women and older individuals. It has been suggested that the prevalence of hypothyroidism and the number of prescriptions for thyroid hormones are increasing. However, despite hypothyroidism being a common medical condition, contemporary data on prevalence, particularly across the various age groups, is limited.

Design

Information regarding number of individuals diagnosed with treated hypothyroidism (defined as patients prescribed levothyroxine) across ten General Practices (total population of 66 843) in the North‐East of England in 2016 was obtained in an anonymized manner. Total as well as age group‐specific point prevalence rates were calculated. In addition, corresponding population data for the United Kingdom were acquired, and national total and age‐specific hypothyroidism prevalence rates were estimated.

Results

The overall prevalence of hypothyroidism in this community sample was 4.5% (n = 3004). Prevalence increased across the age groups from 0.1% in children aged 0‐10 years to 15.1% in those aged more than 90 years. After adjusting for demographic differences between the North‐East England and UK populations, it is estimated that the total UK‐wide prevalence of hypothyroidism in 2016 is 3.6%; affecting more than 2.3 million individuals including nearly 800 000 individuals aged >70 years.

Conclusions

Hypothyroidism affects millions of individuals in the UK and is currently a prevalent diagnosis in more than 1 in 10 individuals aged above 70 years. As the population ages this number is likely to increase. The clinical and economic effects of current management strategies for hypothyroidism, particularly in the older population, need to be evaluated.
Interkinetic nuclear migration in the tracheal and esophageal epithelia of the mouse embryo: Possible implications for tracheo‐esophageal anomalies
Authors: Kaneda Ryo , Saeki Yuko , Getachew Dereje , Matsumoto Akihiro , Furuya Motohide , Ogawa Noriko , Motoya Tomoyuki , Rafiq Ashiq M. , Jahan Esrat , Udagawa Jun , Hashimoto Ryuju , Otani Hiroki
Published: August 2017

Interkinetic nuclear migration (INM) is a cell polarity‐based phenomenon in which progenitor cell nuclei migrate along the apico‐basal axis of the pseudostratified epithelium in synchrony with the cell cycle. INM is suggested to be at least partially cytoskeleton‐dependent and to regulate not only the proliferation/differentiation of stem/progenitor cells but also the localized/overall size and shape of organs/tissues. INM occurs in all three of the germ‐layer derived epithelia, including the endoderm‐derived gut. However, INM has not been documented in the esophagus and respiratory tube arising from the anterior foregut. Esophageal atresia with or without trachea‐esophageal fistula (EA/TEF) is a relatively common developmental defect. Transcription factors and signaling molecules have been implicated in EA/TEF, but the etiology of EA/TEF—which has been suggested to involve cell polarity‐related mechanisms—remains highly controversial. In the present study, we first examined whether INM exists in the trachea and esophagus of mouse embryos at embryonic day 11.5 (E11.5), just after separation of the two tubes from the anterior foregut. By labeling the DNA‐synthesizing stem cell nuclei with 5‐ethynyl‐2′‐deoxyuridine, a nucleotide analogue, and statistically analyzing chronological changes in the distribution pattern of the labeled nuclei by using multidimensional scaling, we showed the existence of INM in both the esophagus and trachea, with differences in the INM magnitude and cycle pattern. We further showed morphological changes from the INM‐based pseudostratified single layer to the stratified multilayer in the esophageal epithelium in association with a temporal loss/perturbation of AB polarity, suggesting a possible relation with the pathogenesis of EA/TEF.
Nevirapine patch testing in Thai human immunodeficiency virus infected patients with nevirapine drug hypersensitivity
Authors: Prasertvit Piyatida , Chareonyingwattana Angkana , Wattanakrai Penpun
Published: August 2017

Background

Antiretroviral drug hypersensitivity in HIV patients is common. Publications have shown that Abacavir (ABC) patch testing is useful in confirming ABC hypersensitivity in 24–50% of cases with a 100% sensitivity of HLA‐B*5701 in patch test positive cases. However, Nevirapine (NVP) patch testing has not been reported.

Objectives

(1) To evaluate the usefulness and safety of NVP patch testing in Thai HIV patients with NVP hypersensitivity. (2) To assess the correlation of positive patch tests with HLA‐B*3505.

Patients and methods

Patients were classified into two groups: (1) study group of 20 HIV NVP hypersensitivity patients and (2) control group of 15 volunteers without NVP hypersensitivity. Both groups were patch tested with purified and commercialized form of NVP in various vehicles.

Results

Two HIV patients with NVP hypersensitivity were patch test positive. All controls tested negative. Three HIV patients were positive for HLA‐B*3505 and the two patients with positive patch testing were both HLA‐B*3505 positive.

Conclusions

NVP patch testing in Thai HIV patients is safe and can be used to help confirm the association between NVP and hypersensitivity skin reactions. NVP patch test results significantly correlated with HLA‐B*3505. The sensitivity of HLA‐B*3505 for positive patch test was 100%.
Screening with doppler ultrasound for carotid artery stenosis in patients with stroke or transient ischaemic attack
Authors: Kristensen Tatiana , Hovind Peter , Iversen Helle K. , Andersen Ulrik B.
Published: August 2017

Introduction

Carotid endarterectomy of symptomatic internal carotid artery stenosis in patients with stroke or transient ischaemic attack reduces the risk of recurrent stroke, particularly if performed within 2 weeks from the first event. We evaluated the efficiency of a screening programme based on Doppler ultrasound in patients hospitalized with stroke or transient ischaemic attack in the stroke centre at Rigshospitalet, Glostrup, Denmark, concerning timeliness of referral to the vascular surgeon and performance of carotid endarterectomy according to national recommendations.

Methods

Prospective study of a consecutive cohort of patients with transient ischaemic attack or stroke, referred for carotid Doppler ultrasound over a one‐year period.

Results

We examined 1390 patients (1048 with stroke, 342 with transient ischaemic attack), 71% within 24 h and 93% within 4 days after admission. Carotid stenosis or occlusion was found in 171 patients (12·3%) and was hemisphere related in 78 patients (5·6%). Among these, 68 (87%) were referred to the vascular department, 94% within 4 days of admission. Carotid endarterectomy was performed in 16 patients, all within 14 days from admission, and was not declined in any patient due to procedural delay.

Conclusions

In a major Danish stroke centre, the national recommended time limit of 4 days in patients with stroke or transient ischaemic attack for screening for carotid stenosis was met in almost all patients. No patients were excluded from surgery as a result of a time limit of 14 days from admission to surgery being exceeded. Of all patients screened, 1·2% underwent carotid endarterectomy.
Simulation of aortopulmonary collateral flow in Fontan patients for use in prediction of interventional outcomes
Authors: Frieberg Petter , Sjöberg Pia , Revstedt Johan , Heiberg Einar , Liuba Petru , Carlsson Marcus
Published: August 2017

Purpose

Patients with complex congenital heart disease may need to be converted to a Fontan circulation with systemic venous return surgically connected to the pulmonary circulation. These patients frequently form aortopulmonary collaterals (APC), that is arterial inflows to the pulmonary artery vascular tree. The aim of this study was to develop a method to calculate the effect of APC on the pulmonary flow distribution based on magnetic resonance imaging (MRI) measurements and computational fluid dynamics simulations in order to enable prediction of interventional outcomes in Fontan patients.

Methods

Patient‐specific models of 11 patients were constructed in a 3D‐design software based on MRI segmentations. APC flow was quantified as the difference between pulmonary venous flow and pulmonary artery flow, measured by MRI. A method was developed to include the modulating effect of the APC flow by calculating the patient‐specific relative pulmonary vascular resistance. Simulations, including interventions with a Y‐graft replacement and a stent dilatation, were validated against MRI results.

Results

The bias between simulated and MRI‐measured fraction of blood to the left lung was 2·9 ± 5·3%. Including the effects of the APC flow in the simulation (n = 6) reduced simulation error from 9·8 ± 7·0% to 5·2 ± 6·3%. Preliminary findings in two patients show that the effect of surgical and catheter interventions could be predicted using the demonstrated methods.

Conclusions

The work demonstrates a novel method to include APC flow in predictive simulations of Fontan hemodynamics. APC flow was found to have a significant contribution to the pulmonary flow distribution in Fontan patients.
Physiological measures in participants with chronic fatigue syndrome, multiple sclerosis and healthy controls following repeated exercise: a pilot study
Authors: Hodges L. D. , Nielsen T. , Baken D.
Published: August 2017

Purpose

To compare physiological responses of chronic fatigue syndrome (CFS/ME), multiple sclerosis (MS) and healthy controls (HC) following a 24‐h repeated exercise test.

Methods

Ten CFS, seven MS and 17 age‐ and gender‐matched healthy controls (10, CFS HC; and seven, MS HC) were recruited. Each participant completed a maximal incremental cycle exercise test on day 1 and again 24 h later. Heart rate (HR), blood pressure (BP), rating of perceived exertion (RPE), oxygen consumption (), carbon dioxide production and workload (WL) were recorded. Data analysis investigated these responses at anaerobic threshold (AT) and peak work rate (PWR).

Results

On day 2, both CFS and MS had significantly reduced max workload compared to HC. On day 2, significant differences were apparent in WL between CFS and CFS HC (93 ± 37 W, 132 ± 42 W, P<0·042). CFS workload decreased on day 2, alongside a decrease in HR but with an increase in (ml kg min−1). This was in comparison with an increase in WL, HR and for CFS HC. MS demonstrated a decreased WL compared to MS HC on both days of the study (D1 81 ± 30 W, 116 ±30 W; D2 84 ± 29 W, 118 ± 36 W); however, patients with MS were able to achieve a higher WL on day 2 alongside MS HC.

Conclusion

These results suggest that exercise exhibits a different physiological response in MS and CFS/ME, demonstrating repeated cardiovascular exercise testing as a valid measure for differentiating between fatigue conditions.
Establishment of estrogen receptor 1 (ESR1)‐knockout medaka: ESR1 is dispensable for sexual development and reproduction in medaka, Oryzias latipes
Authors: Tohyama Saki , Ogino Yukiko , Lange Anke , Myosho Taijun , Kobayashi Tohru , Hirano Yu , Yamada Gen , Sato Tomomi , Tatarazako Norihisa , Tyler Charles R. , Iguchi Taisen , Miyagawa Shinichi
Published: August 2017

Estrogens play fundamental roles in regulating reproductive activities and they act through estrogen receptor (ESR) in all vertebrates. Most vertebrates have two ESR subtypes (ESR1 and ESR2), whereas teleost fish have at least three (Esr1, Esr2a and Esr2b). Intricate functionalization has been suggested among the Esr subtypes, but to date, distinct roles of Esr have been characterized in only a limited number of species. Study of loss‐of‐function in animal models is a powerful tool for application to understanding vertebrate reproductive biology. In the current study, we established esr1 knockout (KO) medaka using a TALEN approach and examined the effects of Esr1 ablation. Unexpectedly, esr1 KO medaka did not show any significant defects in their gonadal development or in their sexual characteristics. Neither male or female esr1 KO medaka exhibited any significant changes in sexual differentiation or reproductive activity compared with wild type controls. Interestingly, however, estrogen‐induced vitellogenin gene expression, an estrogen‐responsive biomarker in fish, was limited in the liver of esr1 KO males. Our findings, in contrast to mammals, indicate that Esr1 is dispensable for normal development and reproduction in medaka. We thus provide an evidence for estrogen receptor functionalization between mammals and fish. Our findings will also benefit interpretation of studies into the toxicological effects of estrogenic chemicals in fish.
Characterization of plasma labile heme in hemolytic conditions
Authors: Gouveia Zélia , Carlos Ana R. , Yuan Xiaojing , Aires‐da‐Silva Frederico , Stocker Roland , Maghzal Ghassan J. , Leal Sónia S. , Gomes Cláudio M. , Todorovic Smilja , Iranzo Olga , Ramos Susana , Santos Ana C. , Hamza Iqbal , Gonçalves João , Soares Miguel P.
Published: August 2017

Extracellular hemoglobin, a byproduct of hemolysis, can release its prosthetic heme groups upon oxidation. This produces metabolically active heme that is exchangeable between acceptor proteins, macromolecules and low molecular weight ligands, termed here labile heme. As it accumulates in plasma labile heme acts in a pro‐oxidant manner and regulates cellular metabolism while exerting pro‐inflammatory and cytotoxic effects that foster the pathogenesis of hemolytic diseases. Here, we developed and characterized a panel of heme‐specific single domain antibodies (sdAbs) that together with a cellular‐based heme reporter assay, allow for quantification and characterization of labile heme in plasma during hemolytic conditions. Using these approaches, we demonstrate that when generated during hemolytic conditions labile heme is bound to plasma molecules with an affinity higher than 10−7 m and that 2–8% (~ 2–5 μm) of the total amount of heme detected in plasma can be internalized by bystander cells, termed here bioavailable heme. Acute, but not chronic, hemolysis is associated with transient reduction of plasma heme‐binding capacity, that is, the ability of plasma molecules to bind labile heme with an affinity higher than 10−7 m. The heme‐specific sdAbs neutralize the pro‐oxidant activity of soluble heme in vitro, suggesting that these maybe used to counter the pathologic effects of labile heme during hemolytic conditions. Finally, we show that heme‐specific sdAbs can be used to visualize cellular heme. In conclusion, we describe a panel of heme‐specific sdAbs that when used with other approaches provide novel insights to the pathophysiology of heme.
POU3F2 participates in cognitive function and adult hippocampal neurogenesis via mammalian‐characteristic amino acid repeats
Authors: Hashizume K. , Yamanaka M. , Ueda S.
Published: August 2017

POU3F2/BRN‐2 is a transcription factor that is mainly expressed in the central nervous system and plays an important role in brain development. The transactivation domain of POU3F2 includes multiple mammalian‐characteristic tandem amino acid repeats (homopolymeric amino acid repeats). We previously generated knock‐in mice (Pou3f2Δ/Δ mice) in which all three homopolymeric amino acid repeats were deleted from the Pou3f2 transactivation domain and identified phenotypic impairments in maternal behavior and pup recognition. Yet, the exact biological implications of homopolymeric repeats are not completely understood. In this study, we investigated cognitive function and hippocampal neurogenesis in Pou3f2Δ/Δ mice. Pou3f2Δ/Δ mice exhibited cognitive impairment in object recognition and object location tests. Immunohistochemistry for doublecortin, a marker of immature neurons, showed a lower number of newborn neurons in the dentate gyrus of adult Pou3f2Δ/Δ mice compared with wild‐type mice. Consistent with this observation, adult Pou3f2Δ/Δ mice had lower numbers of 5‐bromo‐2′‐deoxyuridine (BrdU) and NeuN double‐positive cells at 4 weeks after BrdU injection compared with control mice, indicating the decreased generation of mature granule cells in Pou3f2Δ/Δ mice. Taken together, these results suggest that POU3F2 is involved in cognitive function as well as adult hippocampal neurogenesis, and that homopolymeric amino acid repeats in this gene play a functional role.
Like Father, Like Son: Inheriting and Bequeathing
Authors: Bethencourt Carlos , Kunze Lars
Published: August 2017

This paper incorporates indirect reciprocal behavior in the context of bequeathing decisions into an otherwise standard OLG model. We provide conditions for the existence of a unique steady state with operative bequests. Contrary to standard OLG models, we show that taking into account such behavioral interactions allows one to rationalize both an increasing and U-shaped pattern of the inheritance to GDP ratio over time, consistent with recent empirical evidence. Moreover, the model predicts a nonlinear (U-shaped) relationship between the size of an unfunded social security program and the long-run stock of per capita capital, which in turn provides a novel explanation of the inconclusive empirical findings on the relationship between social security, savings and long-run growth. Ricardian equivalence is shown to hold in a special case of the model.
Presidential Address and record of the Royal Geographical Society (with IBG) AGM 2017
Authors: Crane Nicholas
Published: August 2017

In his second address as President of the Royal Geographical Society (with the Institute of British Geographers), Nicholas Crane illustrated the role geography can play in a shared, popular narrative. He argued that we should consider devoting more attention to promoting accessible geographical narratives with their long‐term emphases on people, places and environment, and less attention to historical narratives with their emphases on documented events limited to the last couple of thousand years.
3′‐Sialyllactose protects against osteoarthritic development by facilitating cartilage homeostasis
Authors: Jeon Jimin , Kang Li‐Jung , Lee Kwang Min , Cho Chanmi , Song Eun Kyung , Kim Wook , Park Tae Joo , Yang Siyoung
Published: August 2017

3′‐Sialyllactose has specific physiological functions in a variety of tissues; however, its effects on osteoarthritic development remain unknown. Here, we demonstrated the function of 3′‐sialyllactose on osteoarthritic cartilage destruction. In vitro and ex vivo, biochemical and histological analysis demonstrated that 3′‐sialyllactose was sufficient to restore the synthesis of Col2a1 and accumulation of sulphated proteoglycan, a critical factor for cartilage regeneration in osteoarthritic development, and blocked the expression of Mmp3, Mmp13 and Cox2 induced by IL‐1β, IL‐6, IL‐17 and TNF‐α, which mediates cartilage degradation. Further, reporter gene assays revealed that the activity of Sox9 as a transcription factor for Col2a1 expression was accelerated by 3′‐sialyllactose, whereas the direct binding of NF‐κB to the Mmp3, Mmp13 and Cox2 promoters was reduced by 3′‐sialyllactose in IL‐1β‐treated chondrocytes. Additionally, IL‐1β induction of Erk phosphorylation and IκB degradation, representing a critical signal pathway for osteoarthritic development, was totally blocked by 3′‐sialyllactose in a dose‐dependent manner. In vivo, 3′‐sialyllactose protected against osteoarthritic cartilage destruction in an osteoarthritis mouse model induced by destabilization of the medial meniscus, as demonstrated by histopathological analysis. Our results strongly suggest that 3′‐sialyllactose may ameliorate osteoarthritic cartilage destruction by cartilage regeneration via promoting Col2a1 production and may inhibit cartilage degradation and inflammation by suppressing Mmp3, Mmp13 and Cox2 expression. The effects of 3′‐sialyllactose could be attributed in part to its regulation of Sox9 or NF‐κB and inhibition of Erk phosphorylation and IκB degradation. Taken together, these effects indicate that 3′‐sialyllactose merits consideration as a natural therapeutic agent for protecting against osteoarthritis.
Systemic administration of bone marrow‐derived cells leads to better uterine engraftment than use of uterine‐derived cells or local injection
Authors: Liu Ying , Tal Reshef , Pluchino Nicola , Mamillapalli Ramanaiah , Taylor Hugh S.
Published: August 2017

Stem cells are recruited to the uterus where they differentiate into endometrial cells and have been suggested as potential therapy for uterine injury such as Asherman's syndrome. However, it is unknown whether local intrauterine injection may result in better stem cell engraftment of the uterus compared with systemic administration, and whether uterine‐derived cells (UDCs) may confer an advantage over BM‐derived cells (BMDCs). Mice underwent local injury to a single uterine horn. Green fluorescent protein (GFP)‐expressing BMDCs, UDCs or saline (control) were injected either intravenously or locally (uterine lumen) into wild‐type recipients. Two or 3 weeks post‐transplant, uterine tissues were collected for fluorescence‐activated cell sorting (FACS) and immunohistochemistry/immunofluorescence studies. Mice injected intravenously with BMDCs or UDCs had increased GFP+ cells recruitment to the non‐injured or injured uterus compared to those injected locally. No significant differences were noted in GFP+ cell recruitment to the injured versus non‐injured horn. In addition, systemic injection of BMDCs led to greater recruitment of GFP+ cells at 2 weeks and 3 weeks compared with UDCs. Immunohistochemical staining demonstrated that GFP+ cells were found in stroma but not in epithelium or blood vessels. Immunofluorescence analysis revealed that GFP+ cells were mostly CD45‐negative, and negative for CD31 and cytokeratin, confirming their stromal identity. In conclusion, the systemic route of administration results in better recruitment of BMDCs or UDCs to the injured uterus than local injection. In addition, BMDCs recruitment to the uterus is greater than UDCs. These findings inform the development of stem cell‐based therapies targeting the uterus.
A novel mutation of adenomatous polyposis coli (APC) gene results in the formation of supernumerary teeth
Authors: Yu Fang , Cai Wenping , Jiang Beizhan , Xu Laijun , Liu Shangfeng , Zhao Shouliang
Published: August 2017

Supernumerary teeth are teeth that are present in addition to normal teeth. Although several hypotheses and some molecular signalling pathways explain the formation of supernumerary teeth, but their exact disease pathogenesis is unknown. To study the molecular mechanisms of supernumerary tooth‐related syndrome (Gardner syndrome), a deeper understanding of the aetiology of supernumerary teeth and the associated syndrome is needed, with the goal of inhibiting disease inheritance via prenatal diagnosis. We recruited a Chinese family with Gardner syndrome. Haematoxylin and eosin staining of supernumerary teeth and colonic polyp lesion biopsies revealed that these patients exhibited significant pathological characteristics. APC gene mutations were detected by PCR and direct sequencing. We revealed the pathological pathway involved in human supernumerary tooth development and the mouse tooth germ development expression profile by RNA sequencing (RNA‐seq). Sequencing analysis revealed that an APC gene mutation in exon 15, namely 4292‐4293‐Del GA, caused Gardner syndrome in this family. This mutation not only initiated the various manifestations typical of Gardner syndrome but also resulted in odontoma and supernumerary teeth in this case. Furthermore, RNA‐seq analysis of human supernumerary teeth suggests that the APC gene is the key gene involved in the development of supernumerary teeth in humans. The mouse tooth germ development expression profile shows that the APC gene plays an important role in tooth germ development. We identified a new mutation in the APC gene that results in supernumerary teeth in association with Gardner syndrome. This information may shed light on the molecular pathogenesis of supernumerary teeth. Gene‐based diagnosis and gene therapy for supernumerary teeth may become available in the future, and our study provides a high‐resolution reference for treating other syndromes associated with supernumerary teeth.
Adaptive changes of telocytes in the urinary bladder of patients affected by neurogenic detrusor overactivity
Authors: Traini Chiara , Fausssone‐Pellegrini Maria‐Simonetta , Guasti Daniele , Del Popolo Giulio , Frizzi Jacopo , Serni Sergio , Vannucchi Maria‐Giuliana
Published: August 2017

Urinary bladder activity involves central and autonomic nervous systems and bladder wall. Studies on the pathogenesis of voiding disorders such as the neurogenic detrusor overactivity (NDO) due to suprasacral spinal cord lesions have emphasized the importance of an abnormal handling of the afferent signals from urothelium and lamina propria (LP). In the LP (and detrusor), three types of telocytes (TC) are present and form a 3D‐network. TC are stromal cells able to form the scaffold that contains and organizes the connective components, to serve as guide for tissue (re)‐modelling, to produce trophic and/or regulatory molecules, to share privileged contacts with the immune cells. Specimens of full thickness bladder wall from NDO patients were collected with the aim to investigate possible changes of the three TC types using histology, immunohistochemistry and transmission electron microscopy. The results show that NDO causes several morphological TC changes without cell loss or network interruption. With the exception of those underlying the urothelium, all the TC display signs of activation (increase in Caveolin1 and caveolae, αSMA and thin filaments, Calreticulin and amount of cisternae of the rough endoplasmic reticulum, CD34, euchromatic nuclei and large nucleoli). In all the specimens, a cell infiltrate, mainly consisting in plasma cells located in the vicinity or taking contacts with the TC, is present. In conclusion, our findings show that NDO causes significant changes of all the TC. Notably, these changes can be interpreted as TC adaptability to the pathological condition likely preserving each of their peculiar functions.
The mechanism of acute fasting‐induced antidepressant‐like effects in mice
Authors: Cui Ranji , Fan Jie , Ge Tongtong , Tang Linda , Li Bingjin
Published: August 2017

Acute fasting induced antidepressant‐like effects. However, the exact brain region and mechanism of these actions are still largely unknown. Therefore, in this study the antidepressant‐like effects of acute fasting on c‐Fos expression and BDNF levels were investigated. Consistent with our previous findings, immobility time was remarkably shortened by 9 hrs fasting in the forced swimming test. Furthermore, these antidepressant‐like effects of 9 fasting were inhibited by a 5‐HT2A/2C receptor agonist (±)‐1‐(2, 5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane hydrochloride (DOI), and the effect of DOI was blocked by pretreatment with a selective 5‐HT2A receptor antagonist ketanserin. Immunohistochemical study has shown that c‐Fos level was significantly increased by 9 hrs fasting in prefrontal cortex but not hippocampus and habenular. Fasting‐induced c‐Fos expression was further enhanced by DOI in prefrontal cortex, and these enhancements were inhibited by ketanserin. The increased BDNF levels by fasting were markedly inhibited by DOI in frontal cortex and hippocampus, and these effects of DOI on BDNF levels were also blocked by ketanserin. These findings suggest that the antidepressant‐like effects of acute fasting may be exerted via 5‐HT2A receptor and particularly sensitive to neural activity in the prefrontal cortex. Furthermore, these antidepressant‐like effects are also mediated by CREB and BDNF pathway in hippocampus and frontal cortex. Therefore, fasting may be potentially helpful against depression.
Ectodysplasin A regulates epithelial barrier function through sonic hedgehog signalling pathway
Authors: Li Sanming , Zhou Jing , Zhang Liying , Li Juan , Yu Jingwen , Ning Ke , Qu Yangluowa , He Hui , Chen Yongxiong , Reinach Peter S. , Liu Chia‐Yang , Liu Zuguo , Li Wei
Published: August 2017

Ectodysplasin A (Eda), a member of the tumour necrosis factor superfamily, plays an important role in ectodermal organ development. An EDA mutation underlies the most common of ectodermal dysplasias, that is X‐linked hypohidrotic ectodermal dysplasia (XLHED) in humans. Even though it lacks a developmental function, the role of Eda during the postnatal stage remains elusive. In this study, we found tight junctional proteins ZO‐1 and claudin‐1 expression is largely reduced in epidermal, corneal and lung epithelia in Eda mutant Tabby mice at different postnatal ages. These declines are associated with tail ulceration, corneal pannus formation and lung infection. Furthermore, topical application of recombinant Eda protein markedly mitigated corneal barrier dysfunction. Using cultures of a human corneal epithelial cell line and Tabby mouse skin tissue explants, Eda up‐regulated expression of ZO‐1 and claudin‐1 through activation of the sonic hedgehog signalling pathway. We conclude that EDA gene expression contributes to the maintenance of epithelial barrier function. Such insight may help efforts to identify novel strategies for improving management of XLHED disease manifestations in a clinical setting.
Down‐regulation of miR‐10a‐5p in synoviocytes contributes to TBX5‐controlled joint inflammation
Authors: Hussain Nazim , Zhu Wenhua , Jiang Congshan , Xu Jing , Wu Xiaoying , Geng Manman , Hussain Safdar , Cai Yongsong , Xu Ke , Xu Peng , Han Yan , Sun Jian , Meng Liesu , Lu Shemin
Published: August 2017

MicroRNAs are considered to play critical roles in the pathogenesis of human inflammatory arthritis, including rheumatoid arthritis (RA). The purpose of this study was to determine the relationship between miR‐10a‐5p and TBX5 in synoviocytes and evaluate their contribution to joint inflammation. The expression of miR‐10a‐5p and TBX5 in the synovium of RA and human synovial sarcoma cell line SW982 stimulated by IL‐1β was determined by RT‐qPCR and Western blotting. The direct interaction between miR‐10a‐5p and TBX5 3′UTR was determined by dual‐luciferase reporter assay in HeLa cells. Mimics and inhibitors of miR‐10a‐5p were transfected into SW982 cells. TBX5 was overexpressed by plasmid transfection or knocked down by RNAi. Proinflammatory cytokines and TLR3 and MMP13 expressions were determined by RT‐qPCR and Western blotting. Down‐regulated expression of miR‐10a‐5p and up‐regulation of TBX5 in human patients with RA were found compared to patients with OA. IL‐1β could reduce miR‐10a‐5p and increase TBX5 expression in SW982 cells in vitro. The direct target relationship between miR‐10a‐5p and 3′UTR of TBX5 was confirmed by luciferase reporter assay. Alterations of miR‐10‐5p after transfection with its mimic and inhibitor caused the related depression and re‐expression of TBX5 and inflammatory factors in SW982 cells. Overexpression of TBX5 after pCMV3‐TBX5 plasmid transfection significantly promoted the production of TLR3, MMP13 and various inflammatory cytokines, while this effect was rescued after knocking down of TBX5 with its specific siRNA. We conclude that miR‐10a‐5p in a relation with TBX5 regulates joint inflammation in arthritis, which would serve as a diagnostic and therapeutic target for RA treatment.
Serum lipid levels in patients with periodontal disease: A meta‐analysis and meta‐regression
Authors: Nepomuceno Rafael , Pigossi Suzane C. , Finoti Livia S. , Orrico Silvana R. P. , Cirelli Joni A. , Barros Silvana P. , Offenbacher Steven , Scarel‐Caminaga Raquel M.
Published: August 2017

Aim

Several papers have considered the potential relationship between periodontitis and lipid parameters. The present systematic review, meta‐analysis and meta‐regression studies focused on investigating whether serum lipid parameter levels were elevated in patients with periodontal disease (PD; without altered systemic conditions) in comparison with periodontally healthy subjects.

Materials and Methods

Eligible studies were those with data about serum lipid parameter levels in non‐smoking subjects with and without chronic periodontitis, who are generally healthy and not taking any medication for dyslipidaemia. Mean differences and 95% confidence intervals for total cholesterol, triglycerides, low‐density lipoprotein (LDL) cholesterol and high‐density lipoprotein (HDL) cholesterol were obtained from all the selected studies.

Results

A total of 19 publications were included for meta‐analysis. Participants with chronic periodontitis presented significantly higher serum levels of LDL and triglycerides (p = .003 and p < .0001, respectively). The total cholesterol was higher in the PD group, but without significant difference in comparison with healthy participants. Significantly (p = .0005) lower HDL serum levels were found in patients with chronic periodontitis than in healthy subjects.

Conclusions

Even considering the limitations of this meta‐analysis, it is suggested that PD is significantly associated with reduction in HDL and elevation of LDL and triglyceride concentrations. This analysis supports the rationale that periodontal disease is associated with lipid metabolic control.
The Effects of Twombly and Iqbal
Authors: Hubbard William H. J.
Published: August 2017

Ever since Twombly and Iqbal introduced the doctrine of plausibility pleading, a cottage industry of legal scholars (including myself) has undertaken to detect the effects of Twombly and Iqbal on litigants and case outcomes. Results so far have been equivocal, and it has been hard to make sense of the disparate methodologies and findings. In this article, I develop a comprehensive yet nontechnical framework for empirically testing the effects of Twombly and Iqbal on lower courts and litigants, taking into account a wide range of confounding factors and the numerous ways in which Twombly and Iqbal may have indirectly affected litigant behavior. Using this framework, I test for effects of Twombly and Iqbal on district court and litigant behavior using two datasets—one of administrative data covering over 700,000 cases, and one of detailed, hand‐ and machine‐coded docket and complaint data covering a representative sample of nearly 2,000 cases. I also review existing findings. I find only limited evidence that Twombly and Iqbal, the two most important pleading cases in 50 years, have had a major effect on the behavior of lawyers and judges across all cases. For represented plaintiffs, rates of dismissal with prejudice have held steady, motions to dismiss remain uncommon, and settlement and filing patterns have not changed appreciably in the wake of Twombly and Iqbal. There is, however, some evidence of effects—potentially major effects—on pro se plaintiffs. Further, while case outcomes for represented plaintiffs have been largely unaffected by Twombly and Iqbal, there is evidence that lawyers changed their pleading and motion practice in the wake of those cases.
The Effect of Tax Expenditures on Automatic Stabilizers: Methods and Evidence
Authors: Kingi Hautahi , Rozema Kyle
Published: August 2017

We study the effect of tax expenditures on the stabilizing power of the tax system. We propose a micro‐simulation strategy that exploits links that we identify between automatic stabilizers, tax expenditures, and effective marginal tax rates. Using U.S. tax return micro data from 2000 to 2010, we estimate that, on average, the mortgage interest deduction and the charitable contributions deduction decreased the ability of the tax system to absorb fluctuations in aggregate consumption by an average of 7.4 percent and 3.9 percent, respectively.
A reciprocal inhibition between ARID1 and MET1 in male and female gametes in Arabidopsis
Authors: Li Lei , Wu Wenye , Zhao Youshang , Zheng Binglian
Published: August 2017

Both female and male gametophytes harbor companion cells and gametes. MET1, a DNA methyltransferase, is down‐regulated in companion cells. However, how MET1 is differentially regulated in gametophytes remains unexplored. ARID1, a transcription factor that is specifically depleted in sperm cells, is occupied by MET1‐dependent CG methylation. Here, we show that MET1 confines ARID1 to the vegetative cell of male gametes, but ARID1 conversely represses MET1 in the central cell of female gametes. Compared to the vegetative cell‐localization in wild type pollen, ARID1 expands to sperm cells in the met1 mutant. To understand whether MET1‐dependent ARID1 inhibition exists during female gametogenesis, we first show that ARID1 is expressed in the megaspore mother cell (MMC), ARID1 but not MET1 is detectable in the central cell at maturity. Interestingly, compared to the absence of MET1 in the central cell and the egg cell of wild type ovules, MET1 significantly accumulates in these two cells in arid1 ovules. Lastly, we show that both ARID1 and MET1 are required for the cell specification of MMC. Collectively, our results uncover a reciprocal dependence between ARID1 and MET1, and provide a clue to further understand how the specification of MMC is likely regulated by DNA methylation.
The polyketide synthase OsPKS2 is essential for pollen exine and Ubisch body patterning in rice
Authors: Zhu Xiaolei , Yu Jing , Shi Jianxin , Tohge Takayuki , Fernie Alisdair R. , Meir Sagit , Aharoni Asaph , Xu Dawei , Zhang Dabing , Liang Wanqi
Published: August 2017

Lipid and phenolic metabolism are important for pollen exine formation. In Arabidopsis, polyketide synthases (PKSs) are essential for both sporopollenin biosynthesis and exine formation. Here, we characterized the role of a polyketide synthase (OsPKS2) in male reproduction of rice (Oryza sativa). Recombinant OsPKS2 catalyzed the condensation of fatty acyl‐CoA with malonyl‐CoA to generate triketide and tetraketide α‐pyrones, the main components of pollen exine. Indeed, the ospks2 mutant had defective exine patterning and was male sterile. However, the mutant showed no significant reduction in sporopollenin accumulation. Compared with the WT (wild type), ospks2 displayed unconfined and amorphous tectum and nexine layers in the exine, and less organized Ubisch bodies. Like the pksb/lap5 mutant of the Arabidopsis ortholog, ospks2 showed broad alterations in the profiles of anther‐related phenolic compounds. However, unlike pksb/lap5, in which most detected phenolics were substantially decreased, ospks2 accumulated higher levels of phenolics. Based on these results and our observation that OsPKS2 is unable to fully restore the exine defects in the pksb/lap5, we propose that PKS proteins have functionally diversified during evolution. Collectively, our results suggest that PKSs represent a conserved and diversified biochemical pathway for anther and pollen development in higher plants.
Potassium channel AKT1 is involved in the auxin‐mediated root growth inhibition in Arabidopsis response to low K+ stress
Authors: Li Juan , Wu Wei‐Hua , Wang Yi
Published: August 2017

The changes in external K+ concentration affect plant root growth. However, the molecular mechanism for perceiving a K+ signal to modulate root growth remains unknown. It is hypothesized that the K+ channel AKT1 is involved in low K+ sensing in the Arabidopsis root and subsequent regulation of root growth. Along with the decline of external K+ concentration, the primary root growth of wild‐type plants was gradually inhibited. However, the primary root of the akt1 mutant could still grow under low K+ (LK) conditions. Application of NAA inhibited akt1 root growth, but promoted wild‐type root growth under LK conditions. By using the ProDR5:GFP and ProPIN1:PIN1‐GFP lines, we found that LK treatment reduced auxin accumulation in wild‐type root tips by degrading PIN1 proteins, which did not occur in the akt1 mutant. The LK‐induced PIN1 degradation may be due to the inhibition of vesicle trafficking of PIN1 proteins. In conclusion, our findings indicate that AKT1 is required for an Arabidopsis response to changes in external K+, and subsequent regulation of K+‐dependent root growth by modulating PIN1 degradation and auxin redistribution in the root.
A meta‐analysis of interview length on reliability and validity
Authors: Thorsteinson Todd J.
Published: August 2017

First impressions are frequently seen as a biasing factor that may prevent an interviewer from forming a comprehensive assessment of the applicant. However, research has found that people can make surprisingly accurate impressions of others based on minimal information. Additional exposure to the applicant would be expected to lead to a more accurate impression, but a previous meta‐analysis on the employment interview found evidence for a negative relationship between the length of the interview and validity. Using a much larger sample of studies, the current meta‐analysis examined whether length of the interview was related to the validity of the interview. In addition, I examined the relation between interview length and reliability. Results revealed that the subset of studies reporting length of interviews yielded reliability and validity estimates consistent with more comprehensive meta‐analyses. Consistent with previous research on consensus judgements of personality, length of the interview was found to be unrelated to reliability. However, contrary to the previous meta‐analysis, validity was also unrelated to the length of the interview.

Practitioner points

Little attention has been given to how the length of time spent interviewing job candidates relates to the reliability and validity of interviews

Length of the interview was not related to reliability or validity of interviews

Results suggest that organizations can implement shorter interviews to save time and money compared to longer interviews, without sacrificing reliability and predictive validity
Perspectives of hospital emergency department staff on trauma‐informed care for injured children: An Australian and New Zealand analysis
Authors: Hoysted Claire , Babl Franz E , Kassam‐Adams Nancy , Landolt Markus A , Jobson Laura , Curtis Sarah , Kharbanda Anupam B , Lyttle Mark D , Parri Niccolò , Stanley Rachel , Alisic Eva
Published: August 2017

Aim

To examine Australian and New Zealand emergency department (ED) staff's training, knowledge and confidence regarding trauma‐informed care for children after trauma, and barriers to implementation.

Methods

ED staff's perspectives on trauma‐informed care were assessed using a web‐based self‐report questionnaire. Participants included 468 ED staff (375 nursing and 111 medical staff) from hospitals in Australia and New Zealand. Data analyses included descriptive statistics, χ2 tests and multiple regressions.

Results

Over 90% of respondents had not received training in trauma‐informed care and almost all respondents (94%) wanted training in this area. While knowledge was associated with a respondent's previous training and profession, confidence was associated with the respondent's previous training, experience level and workplace. Dominant barriers to the implementation of trauma‐informed care were lack of time and lack of training.

Conclusions

There is a need and desire for training and education of Australian and New Zealand ED staff in trauma‐informed care. This study demonstrates that experience alone is not sufficient for the development of knowledge of paediatric traumatic stress reactions and trauma‐informed care practices. Existing education materials could be adapted for use in the ED and to accommodate the training preferences of Australian and New Zealand ED staff.