bluuebunny/crossref_metadata_2025 huggingface dataset:
MeCP2 nuclear dynamics in live neurons results from low and high affinity chromatin interactions
Authors: Piccolo Francesco M. , Liu Zhe , Dong Peng , Hsu Ching-Lung , Stoyanova Elitsa I. , Rao Anjana , Tjian Robert , Heintz Nathaniel
Published: March 2019

Loss of function mutations in Methyl-CpG-binding Protein 2 (MeCP2) cause the severe neurological disorder Rett Syndrome. MeCP2 is a highly abundant nuclear protein particularly enriched in neurons. Although biochemical and genomic analyses of MeCP2-DNA interaction and genomic distribution demonstrate that MeCP2 binding on chromatin is dependent on DNA modification state, the dynamic behavior of individual MeCP2 proteins in live neurons has not been explored. Here we use live-cell single-molecule imaging to assess the detailed kinetic features of MeCP2 in distinct sub-nuclear regions at high spatial and temporal resolution. Surprisingly, we found that, in granule cell nuclei, MeCP2 has unique diffusion and chromatin binding kinetics that are distinct from highly mobile sequence-specific transcription factors (TF) and immobile histone proteins. Approximately, half of MeCP2 is bound to DNA in a transiently stable mode that is similar to TF binding to their cognate sites. The binding of meCP2 to DNA requires its methyl-binding domain (MBD) and is sensitive to the levels of both DNA methylation and hydroxymethylation. However, when not stably bound, MeCP2 moves slowly in the nucleus most closely resembling histone H1.0. The rate of MeCP2 diffusion in compact, granule cell nuclei is determined by weak, transient DNA interactions mediated primarily by the MBD and three AT-hook domains located in the C-terminal portion of the protein. Both the fraction of stably bound MeCP2 and its rate of diffusion depend on the level of chromatin compaction and neuronal cell type. Our data reveal new features of MeCP2 that dictate its dynamic behavior in neuronal nuclei and suggest that the limited nuclear diffusion of MeCP2 in live neurons may contribute to its local impact on chromatin structure and gene expression.
Modulation of kinesin’s load-bearing capacity by force geometry and the microtubule track
Authors: Pyrpassopoulos Serapion , Shuman Henry , Michael Ostap E.
Published: March 2019

Kinesin motors and their associated microtubule tracks are essential for long-distance transport of cellular cargos. Intracellular activity and proper recruitment of kinesins is regulated by biochemical signaling, cargo adaptors, microtubule associated proteins and mechanical forces. In this study, we found that the effect of opposing forces on the kinesin-microtubule attachment duration depends strongly on experimental assay geometry. Using optical tweezers and the conventional single-bead assay we show that detachment of kinesin from the microtubule is likely accelerated by forces vertical to the long-axis of the microtubule due to contact of the single bead with the underlying surface. We used the three-bead assay to minimize the vertical force component and found that when the opposing forces are mainly parallel to the microtubule the median attachment duration between kinesin and microtubules can be up to 10-fold longer than observed using the single-bead assay. Using the three-bead assay, we also found that not all microtubule protofilaments are equivalent interacting substrates for kinesin and that the median attachment duration (median-Δt) of kinesin varies by more than 10-fold, depending on the relative angular position of the forces along the circumference of the microtubule. Thus, depending on the geometry of forces across the microtubule, kinesin can switch from a fast detaching motor (median-Δt < 0.2 s) to a persistent motor that sustains attachment (median-Δt > 3 s) at high forces (5 pN). Our data show that the load-bearing capacity of the kinesin motor is highly variable and can be dramatically affected by off-axis forces and forces across the microtubule lattice which has implications for a range of cellular activities including cell division and organelle transport.

Significance Statement

Kinesins are cytoskeletal motors responsible for the transport of cargoes along microtubules. It is well known that opposing forces decrease kinesin’s speed and run length. In this study, we found that when the pair of opposing forces applied on the kinesin-microtubule complex are parallel to the microtubule, the ability of kinesin to remain attached to the microtubule can vary by more than an order of magnitude depending on the relative azimuthal position of the pair of forces along the periphery of the microtubule. These results reveal a previously unknown versatility of kinesin’s load bearing capacity and as such have implications for the potential physiological roles of kinesin in a wide range of cell activities, including organelle transport and cell division.
Do Islamic banks need to earn extra profits?
Authors: Suzuki Yasushi , Uddin S.M. Sohrab , Sigit Pramono
Published: March 2019

Purpose

This paper aims to draw upon existing debate over “financial sector rent” (bank rent) to analyze the current pattern of financing of Bangladeshi and Indonesian Islamic banks during the period of 2011 and 2015.

Design/methodology/approach

The empirical evidence through a comparative approach of analyzing the performance of Islamic banks with that of conventional banks in respective countries – two of the largest countries where majority of the population are Muslims – is drawn to demonstrate the objective.

Findings

While Islamic banks in Bangladesh are primarily concentrating on the murabaha (mark-up contract) mode of financing, some transactions under musharaka (partnership/equity-based contract) are observed in the Indonesian Islamic banking sector. This anomaly in Indonesia can be explained by the nature of their musharaka financing which is not of the purely “participatory” financing type. As a result, we can observe the quasi-murabaha syndrome in Indonesian Islamic banking sector. The concentration of asset-based financing including consumers’ financing (hire purchase) in the credit portfolio gives Islamic banks relatively higher Islamic bank rent opportunity for protecting their “franchise value” as Sharīʿah-compliant (Islamic law-compliant) lenders. However, Indonesian Islamic banks share a still infant Islamic banking market, and enjoy less rent opportunity under a severe competition with conventional banks.

Research limitations/implications

The bank rent approach suggests that the syndrome observed both in Bangladesh and Indonesia can be ironically justifiable. Moreover, the mode of profit-and-loss sharing provides, in practice, an idea of the difficulty in managing the participatory financing embedded with high credit risk. Under this scenario, it is necessary for Islamic scholars and the regulatory authority to design an appropriate financial architecture, enabling Islamic banks to avail the benefit from a wider variety of Sharīʿah-based Islamic financing.

Originality/value

This paper expands the newly emerged concept of “Islamic bank rent” to make sense of the murabaha syndrome in Bangladesh and the quasi-murabaha syndrome in Indonesia. This approach also contributes to clarifying the unique risk and cost to be compensated with the spreads that Islamic banks are expected to earn.
Surgical strategy for neuroendocrine liver metastases
Authors: Fung Andrew Kai‐Yip , Chong Charing Ching‐Ning
Published: March 2019

Introduction

There are no established strategies for the surgical management of neuroendocrine liver metastases. Surgical treatment options include liver resection, liver transplantation and debulking hepatectomy. Other liver‐directed therapies include local ablation and transarterial embolization.

Aim

In the present review, we discuss the outcomes of the different surgical treatment modalities for neuroendocrine liver metastases.

Patients and methods

A review of the published literature on the surgical management of neuroendocrine liver metastases was undertaken.

Results

Liver resection is the curative treatment of choice for patients with grade 1 or 2 liver metastases without concurrent extra‐hepatic disease. Liver transplantation is another potentially curative therapy. Debulking hepatectomy might be indicated for symptomatic neuroendocrine liver disease, whereas liver ‐directed local ablative and trans‐arterial treatments should be considered for patients not suitable for liver resection or transplantation.

Conclusions

Hepatectomy and liver transplanatation should be offered to patients with resectable neuroendocrine liver metastases in the absence of extrahepatic metastases.
Risk aversion and land allocation between annual and perennial crops in semisubsistence farming: a stochastic optimization approach
Authors: Ouattara Pierre D. , Kouassi Eugene , Egbendéwé Aklesso Y. G. , Akinkugbe Oluyele
Published: March 2019

This article analyzes the effect of production uncertainty on farmland allocation decisions between perennial and annual crops, focusing on a representative farmer's attitude toward risk. A dynamic stochastic optimization model that considers net planting—the difference between new plantings and removals of perennial crops that achieve full production cycle—is used. The effect of uncertainty on the representative farmer's decisions to increase or decrease perennial crops’ acreage, on the optimal path, is examined. Our results reveal that the response of optimal path of net planting to uncertainty related to perennial crop production is highly affected by the farmer's attitude toward risk. A risk‐averse or a low‐risk loving farmer tends to reduce land allocation to perennial crops under uncertainty, while a high‐risk loving farmer will do exactly the opposite. Also, due to disutility of farming, the farmer tends to reduce land allocation to perennial crops when prices are high enough for him to attain a desired income level expectation. One implication of this research is the need for mechanization—in sub‐Saharan countries in particular—that increases per‐acreage yield and output in semisubsistence agriculture.
N6‐Methyladenosine detected in RNA of testicular germ cell tumors is controlled by METTL3, ALKBH5, YTHDC1/F1/F2, and HNRNPC as writers, erasers, and readers
Authors: Nettersheim D. , Berger D. , Jostes S. , Kristiansen G. , Lochnit G. , Schorle H.
Published: March 2019

Background

Type II testicular germ cell tumors (GCTs) arise from a common precursor lesion (germ cell neoplasia in situ) and are stratified into seminomas and non‐seminomas, which differ considerably in morphology, gene expression, and epigenetic landscape. The N6‐methyladenosine (6mA) epigenetic modification is the most abundant modification in mRNA and is also detectable in eukaryotic DNA. The functional role of 6mA is not fully understood, but 6mA residues may influence transcription by affecting splicing, miRNA processing, and mRNA stability. Additionally, the methyl group of 6mA destabilizes Watson–Crick base‐pairing affecting RNA structure and protein binding.

Objectives

Here, we analyzed the presence of the 6mA epigenetic modification in germ cells and GCT tissues and cell lines.

Materials and methods

We screened for the presence of 6mA in DNA and RNA by immunohistochemistry, mass spectrometry or ELISA‐based quantification assays. Additionally, expression of 6mA writer‐, eraser‐ and reader‐factors was analyzed by microarrays, qRT‐PCR, western blotting and screening of public databases.

Results

We demonstrate that 6mA is detectable in RNA, but not DNA, of GCT cell lines and tissues, fibroblasts, and Sertoli cells as well as germ cells of different developmental stages. Based on expression analyses, our results suggest METTL3, ALKBH5, YTHDC1, YTHDF1, YTHDF2 and HNRNPC as main writers, erasers, and readers of the 6mA modification in GCTs.

Discussion

Owing to the lack of 6mA in DNA of GCTs, a functional role in regulating DNA transcription can be excluded. Interestingly, expression levels of 6mA regulators are comparable between tumor and normal tissues/cells, suggesting a similar mechanism of 6mA regulation in RNA. Finally, we demonstrate that 6mA levels in RNA increase upon differentiation of GCT cell lines, suggesting a role of 6mA in cell fate decisions.

Conclusion

In summary, our data provide the starting point for further experiments deciphering the role of 6mA in the RNA of GCTs.
Birthweight discordance and neonatal morbidity in twin pregnancies: A systematic review and meta‐analysis
Authors: Di Mascio Daniele , Acharya Ganesh , Khalil Asma , Odibo Anthony , Prefumo Federico , Liberati Marco , Buca Danilo , Manzoli Lamberto , Flacco Maria E. , Brunelli Roberto , Benedetti Panici Pierluigi , D'Antonio Francesco
Published: March 2019

Introduction

The aim of this systematic review was to quantify the association between birthweight discordance and neonatal morbidity in twin pregnancies.

Material and methods

MEDLINE, Embase and Cinahl databases were searched. Studies reporting the occurrence of morbidity in twins affected compared with those not affected by birthweight discordance were included. The primary outcome was composite neonatal morbidity (including neurological, respiratory, infectious morbidities, abnormal acid‐base status and necrotizing enterocolitis). The secondary outcomes were the individual morbidities. Sub‐group analysis according to chorionicity, gestational age at birth and fetal weight (smaller vs larger twin) was also performed. Random‐effect head‐to‐head meta‐analyses were used to analyze the data.

Results

Twenty studies (10 851 twin pregnancies) were included. The risk of composite morbidity was significantly higher in the pregnancies with birthweight discordance ≥15% (odds ratio [OR] 1.4, 95% confidence interval [CI] 1.0‐1.9), ≥20% (OR 2.2, 95% CI 1.40‐3.45), ≥25% (OR 2.5, 95% CI 1.8‐3.6), and ≥30% (OR 3.4, 95% CI 2.2‐3.2). In dichorionic twins, birthweight discordance ≥15% (OR 2.4, 95% CI 1.65‐3.46), ≥20% (OR 2.2, 95% CI 1.3‐3.8), ≥25% (OR 2.7, 95% CI 1.4‐5.1) and ≥30% (OR 3.6, 95% CI 2.3‐5.7) were all significantly associated with composite neonatal morbidity. Analysis of monochorionic twins was hampered by the very small number of included studies, which precluded adequate statistical power. Monochorionic twins with a birthweight discordance ≥20% were at significantly higher risk of composite neonatal morbidity (OR 2.2, 95% CI 1.1‐4.9) compared with those presenting with lesser degree of discordance. When stratifying the analysis according to gestational age at birth and fetal size, twins with birthweight discordance ≥15%, 20%, 25% and 30% delivered at ≥34 weeks were at higher risk of neonatal morbidity compared with controls, but there was no difference in the risk of morbidity between the larger and the smaller twin in the discordant pair.

Conclusions

Birthweight discordance is associated with neonatal morbidity in twin pregnancies. The strength of this association persists for dichorionic twins. It was not possible to extrapolate robust evidence on monochorionic twins due to the low power of the analysis due to the small number of included studies.
Repair of the penile suspensory ligament for congenital and acquired pathology
Authors: Ralph Oliver , Shroff Nikita , Anfosso Mattia , Blecher Gideon , Ralph David
Published: March 2019

Objective

To review the mechanisms and patient outcomes for men presenting with abnormalities of the penile suspensory ligament (PSL) and their correction.

Patients and Methods

We conducted a retrospective review of a total of 118 patients who presented with a variety of PSL abnormalities that necessitated surgical repair from 1993 to 2018. The patients mean (range) age at presentation was 29 (12–60) years with a mean (range) follow up of 8 months (3 months–12 years). The diagnosis was made clinically, often with a history of penile instability, pain or curvature/torsion, which was confirmed on artificial erection testing. Nocturnal tumescent testing and magnetic resonance imaging were used where necessary. The surgical repair was performed by placing non‐absorbable sutures between the tunica albuginea of the penis and the symphysis pubis. Postoperative outcomes were reported in the clinic by direct questioning and a repeat of the investigations above when patients were unsatisfied with the result.

Results

The aetiologies and surgical indications in the 118 patients included: abnormality subsequent to sexual trauma (n = 66); congenital curvature of penis and/or congenital absence/laxity of the ligament (n = 37); Peyronie's disease (n = 8); and venogenic erectile dysfunction (ED; n = 7). A good surgical result, as defined by stabilization and straightening of the penis and a return to normal sexual function, was achieved in 85% of the patients and 82% were very satisfied with the outcome. Complications included long‐term ED in four patients.

Conclusion

Abnormalities of the PSL are uncommon and often subtle, but with the appropriate diagnosis, a good cosmetic and functional result is usually achievable.
Synthesis, SAR and docking studies of substituted aryl phenylthiazolyl phenylcarboxamide as potential protein tyrosine phosphatase 1B (PTP1B) inhibitors
Authors: Varshney Kanika , Gupta Amit K. , Rawat Arun , Srivastava Rohit , Mishra Akansha , Saxena Mridula , Srivastava Arvind K. , Jain Sudha , Saxena Anil K.
Published: March 2019

In our continued effort to discover novel PTP1B inhibitor with improved in vivo activity, we attempted to optimize our previously discovered lead compound by replacing the sulfonyl group with benzoyl group to yield compound II. Additional structural modifications were performed on compound II to yield a series of 24 aryl phenylthiazolyl phenylcarboxamides as potential PTP1B inhibitors. Of the 24 tested, 6 compounds showed good PTP1B inhibitory activity while compound 38 as the most promising one. The plausible PTP1B‐binding site interaction of compound 38 showed favourable binding similar to known PTP1B binders and suggests its selectivity towards PTP1B. Compound 38 also showed promising antihyperglycaemic, antidyslipidaemic and insulin resistant reversal activities in vivo in STZ model and db/db mice model. Altogether, the compound 38 presents an excellent candidate for future PTP1B targeted drug discovery.
Multi‐target, ensemble‐based virtual screening yields novel allosteric KRAS inhibitors at high success rate
Authors: Gupta Amit K. , Wang Xu , Pagba Cynthia V. , Prakash Priyanka , Sarkar‐Banerjee Suparna , Putkey John , Gorfe Alemayehu A.
Published: March 2019

RAS mutations account for >15% of all human tumors, and of these ~85% are due to mutations in a particular RAS gene: KRAS. Recent studies revealed that KRAS harbors four druggable allosteric sites. Here, we have (a) used molecular simulations to generate ensembles of wild type and four major oncogenic KRAS mutants (G12V, G12D, G13D, and Q61H); (b) characterized the druggability of each allosteric pocket in each protein; (c) conducted extensive ensemble‐based virtual screening using pocket‐tailored ligand libraries; (d) prioritized hits through hierarchical postdocking analysis; and (e) validated predicted hits with NMR. Of the 785 diverse potential hits identified by our in silico analysis, we tested 90 for their ability to bind KRAS using NMR and found that nine cause backbone amide chemical shift perturbations of residues near the functionally responsive switch loops, suggesting potential binding. We conducted detailed biophysical analyses on a novel indole‐based compound to demonstrate the potential of our workflow to yield lead compounds. We believe the detailed information documented in this work regarding the druggability profile of each allosteric site and the chemical fingerprints of compounds that target them will serve as vital resources for future structure‐based drug design efforts against KRAS, a high‐value target for cancer therapy.
Reversible male hypogonadotropic hypogonadism due to energy deficit
Authors: Wong Henry K. , Hoermann Rudolf , Grossmann Mathis
Published: March 2019

Context

Calorie restriction and overtraining are increasingly seen in young men who suffer from increasing societal pressure to attain a perceived ideal male body image. The resulting energy deficit can lead to multiple endocrine consequences, including suppression of the male gonadal axis.

Design

We reviewed the literature, including two unpublished cases.

Results

We identified 23 cases, aged median (range) 20 years (16‐33), with a body mass index of 15.9 kg/m2 (12.5‐20.5). Total testosterone was 3.0 nmol/L (0.6‐21.3), and luteinizing hormone (LH) 1.2 mIU/L (<0.2‐7.5), with 91% of cases demonstrating hypogonadotropic hypogonadism. Associated findings included evidence of growth hormone resistance (increased growth hormone in 57% and low insulin‐like growth factor‐1 in 71%), hypercortisolaemia (50%) and a nonthyroidal illness picture (67%). In cases with longitudinal measurements following weight regain, serum testosterone (n = 14) increased from median [interquartile range] 3.2 nmol/L [1.9‐5.1] to 14.3 nmol/L [9.3‐21.2] (P < 0.001), and LH (n = 8) from 1.2 IU/L [0.8‐1.8] to 3.5 IU/L [3.3‐4.3] (P = 0.008).

Conclusions

Hypogonadotropic hypogonadism can occur in the context of energy deprivation in young otherwise healthy men and may be underrecognized. The evidence suggests that gonadal axis suppression and associated hormonal abnormalities represent an adaptive response to increased physiological stress and total body energy deficit. The pathophysiology likely involves hypothalamic suppression due to dysregulation of leptin, ghrelin and pro‐inflammatory cytokines. The gonadal axis suppression is functional, because it can be reversible with weight gain. Treatment should focus on reversing the existing energy deficit to achieve a healthy body weight, including psychiatric input where required.
Utility of experimental animal models of myasthenia gravis for the elucidation of pathogenic mechanisms and development of new medications
Authors: Mori Shuuichi , Shigemoto Kazuhiro
Published: March 2019

Myasthenia gravis (MG) is an autoimmune disease characterized by ptosis, fatigue and muscle weakness, caused by the association of pathogenic autoantibodies with postsynaptic membrane proteins at neuromuscular junctions. Although various autoantibodies have been found in sera from patients with MG, causal relationships with MG have not been shown for most antibodies. Establishment of the pathogenicity of candidate antibodies with experimental animal models of myasthenia gravis is indispensable. The pathogenicity of autoantibodies against acetylcholine receptors and muscle‐specific kinase has been confirmed by active immunization with purified antigens or by passive transfer of autoantibodies from patients with MG. Furthermore, animal models of MG have shown not only the pathogenic mechanisms underlying the manifestation of muscle weakness and atrophy observed in patients with MG, but also the efficacy of novel therapies and the adverse effects of therapeutic drugs. Here, we review the contributions of animal MG models to the elucidation of the pathogenic mechanisms of MG and the development of medications for the disease.
Bringing the Kingdom to the City: Mission as Placemaking Practice amongst Kenyan Pentecostals in London
Authors: Fesenmyer Leslie
Published: March 2019

Kenyan Pentecostals in London (re)frame their migration as a “mission” to bring the United Kingdom back into the Kingdom of God. Focusing on the case of one church founded in the diaspora, this article examines how the pastor and church members try to realize this mission by exploring the kind of place they imagine God’s Kingdom to be and their efforts to create it in London. The “spatial turn” in studies of religion has followed two general trajectories, broadly referred to as the politics and the poetics of space. Studies of Pentecostal placemaking in particular have examined how Pentecostals use church‐planting as a strategy of territorialization, by which they make their presence seen and felt in specific localities, as well as how they phenomenologically “do” space. This article contributes to these discussions by elucidating a particular form of sociality as an important aspect of religious placemaking. In doing so, I argue that Pentecostal projects of self‐making and placemaking converge in what I refer to as “socializing space.” At the same time, through its focus on an independent church, the article extends our understanding of African diasporic churches beyond the well‐studied and ‐resourced transnational African Pentecostal networks and megachurches. [Pentecostalism; Placemaking; London; Kenya; African Diaspora]
ENTREPRENEURSHIP AND JOB LOCK: THE INTERACTION BETWEEN TAX SUBSIDIES AND HEALTH INSURANCE REGULATIONS
Authors: Nikpay Sayeh S.
Published: March 2019

This paper demonstrates that health insurance tax subsidies increase self‐employment, but that the effect differs substantially based on nongroup market regulations and health status. Using the Panel Study of Income Dynamics, I show that households that cannot purchase health insurance because of a preexisting condition do not respond to tax subsidies in states in which they would be denied insurance, but they respond strongly in states in which they face risk‐rated premiums. Households respond similarly to tax subsidies in states with nongroup market regulations similar to those established by the Affordable Care Act, regardless of preexisting conditions. (JEL H20, I13, J30)
Is melanocyte density our last hope? Comparison of histologic features of photodamaged skin and melanoma in situ after staged surgical excision with concurrent scouting biopsies
Authors: Speiser Jodi , Tao Joy , Champlain Amanda , Moy Lauren , Janeczek Monica , Omman Reeba , Mudaliar Kumaran , Tung Rebecca
Published: March 2019

Differentiating melanocytic hyperplasia (MH) on photodamaged skin from junctional lentiginous melanocytic proliferations (JLMP), early evolving melanoma in situ (MIS), or the periphery of a lesion of MIS on staged excision can be challenging. Although previous cross‐sectional studies have elucidated important criteria for distinguishing MH on photodamaged skin from more concerning lesions, this study highlights a technique to treat JLMP and MIS with staged mapped excision and baseline scouting biopsies of adjacent nonlesional photodamaged skin to assist in determination of surgical margin clearance. Additionally, we compare the lesional and photodamaged control biopsies from the same patient to evaluate relevant histologic criteria that may be used to distinguish MH in photodamaged skin from JLMP/MIS, while minimizing confounding factors. There was a statistically significant difference (P ≤ 0.05) found for melanocyte density, irregular melanocyte distribution, melanocyte clustering, follicular infundibulum involvement, and nesting. However, criteria such as nesting, epithelioid cells and melanocyte clustering were seen in both photodamaged skin and MIS. These findings underscore the fact that histologic features of photodamaged skin can overlap with the histopathological features of MIS. Of all of the criteria evaluated, melanocytic density was the most objective histologic criterion and did not show overlap between the sun‐damaged and JLMP/MIS groups.
A missense mutation in damage‐specificDNAbinding protein 2 is a genetic risk factor for ocular squamous cell carcinoma in Belgian horses
Authors: Knickelbein K. E. , Lassaline M. E. , Singer‐Berk M. , Reilly C. M. , Clode A. B. , Famula T. R. , Michau T. M. , Bellone R. R.
Published: March 2019

Background

Belgian horses are commonly affected with ocular squamous cell carcinoma (SCC), the most common cancer of the equine eye. A missense mutation in damage‐specificDNAbinding protein 2 (DDB2c.1013C>T, p.Thr338Met) has been established as a recessive genetic risk factor for ocularSCCin the Haflinger breed. A sample of Belgian horses with unknownSCCphenotype was shown to possess this variant at a similar frequency to the Haflinger breed. Retrospective studies indicate that chestnut coat colour may predispose to the development ofSCC.

Objectives

To determine ifDDB2c.1013C>Tis a risk factor for ocularSCCin a strictly phenotyped sample of Belgian horses. To investigate associations between coat colour loci genotypes and ocularSCC.

Study design

Retrospective and prospective case identification, genetic investigation.

Methods

GenomicDNAwas isolated from blood, hair or formalin‐fixed paraffin‐embedded tissue from 25 Belgian horses with histologically confirmed ocularSCCand 18 unaffected Belgian horses. Association testing of 34 single nucleotide variants from 11 genomic loci and genotyping forDDB2c.1013C>Tand coat colour alleles were performed. Exons ofDDB2were sequenced in four cases and two controls. Associations were analysed by Chi‐square or Fisher's exact tests and relative risk was calculated.

Results

Homozygosity forDDB2c.1013C>Twas significantly associated with ocularSCC(P = 7.4 × 10−7). Seventy‐six per cent of affected horses were homozygous for the variant. Relative risk for homozygous horses developingSCCwas 4.0 (P = 1.0 × 10−4). SequencingDDB2did not identify a variant more concordant with disease phenotype. An association between disease and coat colour loci was not identified.

Main limitations

Phenotyping was determined at a single timepoint. Each included horse genotyped as chestnut, so association with thisMC1Rvariant could not be investigated.

Conclusions

A missense variant,DDB2c.1013C>T, p.Thr338Met, is a risk factor for ocularSCCin Belgian horses. A genetic risk test is commercially available.
Dead Sea minerals: New findings on skin and the biology beyond
Authors: Portugal‐Cohen Meital , Cohen Dror , Ish‐Shalom Eliran , Laor‐Costa Yaara , Ma'or Ze'evi
Published: March 2019

Background

Therapeutic effects of Dead Sea (DS) minerals are well established, and their unique combination is analysed and reported. DS water (DSW) is a key source for DS minerals, and various studies report the capability of DSW to alleviate symptoms of different skin disorders and to contribute to skin maintenance. However, the biological mechanisms beyond reported effects are not fully understood yet.

Objective

To elucidate the effect of topically applied DSW via the expression of different skin biomarkers related to barrier function, homeostasis, inflammation and irritation.

Methods

In vitro skin equivalents and ex vivo human skin organ culture were used to assess the biological effects of DSW. Epidermal barrier protein expression and DSW ions transdermal penetration were analysed on skin equivalents. β‐endorphin secretion was tested on human skin organ culture. The capability of DSW to protect against skin inflammation and irritation was tested on ex vivo human skin organ culture by lipopolysaccharides and sodium dodecyl sulphate addition, respectively.

Results

Topical application of DSW encouraged the expression of the barrier‐related proteins: filaggrin, involucrin and transglutaminase, while transdermal penetration of calcium ions was not detected. Additionally, DSW application had increased skin secretion of β‐endorphin and attenuated the expression of inflammatory and irritation‐related cytokines.

Conclusions

This study reports new findings of DSW effects on skin. Signalling pathway activation is proposed as a key step that may result in a vast range of proven biological activities following skin exposure to DS minerals, and specifically DSW.
Molecular and structural characterization of a TEAD mutation at the origin of Sveinsson's chorioretinal atrophy
Authors: Bokhovchuk Fedir , Mesrouze Yannick , Izaac Aude , Meyerhofer Marco , Zimmermann Catherine , Fontana Patrizia , Schmelzle Tobias , Erdmann Dirk , Furet Pascal , Kallen Joerg , Chène Patrick
Published: March 2019

Four TEAD transcription factors (TEAD1–4) mediate the signalling output of the Hippo pathway that controls organ size in humans. TEAD transcriptional activity is regulated via interactions with the YAP, TAZ and VGLL proteins. A mutation in the TEAD1 gene, Tyr421His, has been identified in patients suffering from Sveinsson's chorioretinal atrophy (SCA), an autosomal dominant eye disease. This mutation prevents the YAP/TAZ:TEAD1 interaction. In this study, we measure the affinity of YAP, TAZ and VGLL1 for the four human TEADs and find that they have a similar affinity for all TEADs. We quantitate the effect of the mutation found in SCA patients and show that it destabilizes the YAP/TAZ:TEAD interaction by about 3 kcal·mol−1. We determine the structure of YAP in complex with this mutant form of TEAD and show that the histidine residue adopts different conformations at the binding interface. The presence of this flexible residue induces the destabilization of several H‐bonds and the loss of van der Waals contacts, which explains why the Tyr421HisTEAD1 mutation has such a large destabilizing effect on the formation of the YAP:TEAD complex.

Database

The crystallographic data have been deposited at the RSCB Protein Data Bank (PDB, www.pdb.org) with the access codes: 6HIL (wtYAP:Tyr421HisTEAD1), 6HIK (wtYAP:Tyr429HisTEAD4)
Integration in a depot‐based decentralized biorefinery system: Corn stover‐based cellulosic biofuel
Authors: Kim Seungdo , Dale Bruce E. , Jin Mingjie , Thelen Kurt D. , Zhang Xuesong , Meier Paul , Reddy Ashwan Daram , Jones Curtis Dinneen , Cesar Izaurralde Roberto , Balan Venkatesh , Runge Troy , Sharara Mahmoud
Published: March 2019

The current or “conventional” paradigm for producing process energy in a biorefinery processing cellulosic biomass is on‐site energy recovery through combustion of residual solids and biogas generated by the process. Excess electricity is then exported, resulting in large greenhouse gas (GHG) credits. However, this approach will cause lifecycle GHG emissions of biofuels to increase as more renewable energy sources (wind, solar, etc.) participate in grid‐electricity generation, and the GHG credits from displacing fossil fuel decrease. To overcome this drawback, a decentralized (depot‐based) biorefinery can be integrated with a coal‐fired power plant near a large urban area. In an integrated, decentralized, depot‐based biorefinery (IDB), the residual solids are co‐fired with coal either in the adjacent power plant or in coal‐fired boilers elsewhere to displace coal. An IDB system does not rely on indirect GHG credits through grid‐electricity displacement. In an IDB system, biogas from the wastewater treatment facility is also upgraded to biomethane and used as a transportation biofuel. The GHG savings per unit of cropland in the IDB systems (2.7–2.9 MgCO2/ha) are 1.5–1.6 fold greater than those in a conventional centralized system (1.7–1.8 MgCO2/ha). Importantly, the biofuel selling price in the IDBs is lower by 28–30 cents per gasoline‐equivalent liter than in the conventional centralized system. Furthermore, the total capital investment per annual biofuel volume in the IDB is much lower (by ~80%) than that in the conventional centralized system. Therefore, utilization of biomethane and residual solids in the IDB systems leads to much lower biofuel selling prices and significantly greater GHG savings per unit of cropland participating in the biorefinery system compared to the conventional centralized biorefineries.
Thinking Sexual Difference with (and against) Adriana Cavarero: On the Ethics and Politics of Care
Authors: Ryan Kevin
Published: March 2019

This article engages with Adriana Cavarero's framing of sexual difference, specifically in terms of how this displaces “bodies that queer” (Volcano 2013). For Cavarero, the narratable self is inescapably relational and characterized by vulnerability, which is how ethics arises in the form of a decision between caring and wounding. At the same time, Cavarero's deconstructive method of appropriating stereotypes restricts the scope of sexual difference to dimorphism. In examining the implications of this, I build on the work of Michel Foucault and Judith Butler by looking to the intersexed life of Adélaïde Herculine Barbin, whose suicide in 1868 at the age of twenty‐nine was precipitated not through malice or cruelty, but through concerted care. This mode of care is anchored in the apparent self‐evidence of how we see and how we think with and through narratives that sediment in orders of power/knowledge. While agreeing with Cavarero's critique of the autonomous “I,” the article nevertheless argues for authorial audacity—the courage to name oneself—as a way of subverting asymmetrical power relations, including those that make it possible to inadvertently generate suffering through care.
On Black Women, “In Defense of Transracialism,” and Imperial Harm
Authors: Russell Camisha
Published: March 2019

This essay is a response to the events surroundingHypatia's publication of “In Defense of Transracialism.” It does not take up the question of “transracialism” itself, but rather attempts to shed light both on what some black women may have experienced following from the publication of the article and on how we might understand this experience as harm. It also suggests one way for feminist journals to reduce the likelihood of similar harms occurring in the future. I begin by describing a discussion that occurred in my classroom that bears some resemblance to the much larger debate that emerged aroundHypatia. Next, I elaborate a concept of imperial harm. I then address how this concept comes to be relevant to the experience of black women within the discipline of philosophy in general, before briefly describing how academic feminism (including feminist philosophy) has served as a particular site of imperial harm for black women. Finally, touching on the idea of expressive harm, I conclude with an appeal for the adoption of more feminist publication ethics.
Large‐sized La2O3‐TiO2 high refractive glasses with low SiO2 fraction by hot‐press sintering
Authors: Han Jianjun , Wang Zhui , Li Jianqiang , Li Xiaoyu , Li Jiangtao , He Gang , Xie Jun
Published: March 2019

Owing to the ultrahigh refractive index, La2O3‐TiO2 glass is regarded as a promising candidate material in the field of lens, gemstones, and many other optics. However, due to its extremely low glass‐forming ability, it can only be obtained by rapid solidification processes such as melt quench or containerless solidification methods, leading to the limited size of as‐solidified products (for example, 1‐10 mm for containerless solidified sample), that are severely deferring the application of this novel high refractive glass. In this work, we aimed at preparing the larger sized bulk glasses over 10 mm, La2O3‐TiO2 glasses were successfully prepared by hot‐press sintering within the glass kinetic window. A small amount addition of SiO2 was found to effectively increase the glass‐forming ability while keeping high refractive index. When the content of SiO2 was 15 mol%, its transmittance could reach 54% at 800 nm and 72% in the infrared region (1 mm thick). Meanwhile, its refractive index could keep ultrahigh value above 2.14. And the sintering mechanism was studied according to the sintering shrinkage curve. It indicates that the plastic flow was the main mass transfer way in the densification process.
Laying new foundations for 21st century community mental health services: An Australian perspective
Authors: Williams Theresa Maureen , Smith Geoffrey Paul
Published: March 2019

While there has been a significant increase in investment in community mental health in Australia since the advent of the National Mental Health Strategy in the early 1990s, there has been little guidance on service design and delivery. This has led to a growing diversity of approaches and concern about the adequacy of care with repeated calls for a system overhaul. Consumers and carers have very largely been absent from decision‐making about service design and development which has led to a system primarily designed by healthcare professionals. However, with the emergence of recovery as a core principle in mental health, it is time for consumers and carers to be centrally engaged in co‐designing services with service providers. This raises the question of whether dominant service delivery models – such as the growth of specialist teams/services, the changing balance between profession‐specific and generic case management roles in multidisciplinary teams, and the separation of inpatient from community care – will prevail. Contentious issues in these three service delivery areas are outlined to stimulate debate and highlight the pressing need for national guidance on the configuration of community mental health services. Building on the lessons learned from the first National Mental Health Strategy, we outline a proposal for a co‐designed National Framework for Community Mental Health Services to guide the delivery of care in a way which satisfies the aspirations of consumers, carers, and mental health professionals alike.
Cold sintering and microwave dielectric properties of dense HBO2‐II ceramics
Authors: Hong Wen Bin , Li Lei , Yan Han , Chen Xiang Ming
Published: March 2019

HBO2‐II ceramics were prepared by cold sintering with 10wt% dehydrated ethanol as the transient liquid phase. When the processing temperature is 30°C, the relative density of the mechanically robust HBO2‐II ceramics increases from 77.5% to 84.5% with increasing the uniaxial pressure from 200 to 500 MPa. It changes less than 0.2% for higher pressure up to 700 MPa. Under a constant uniaxial pressure of 500 MPa, the relative density further increases to 94.7% for the processing temperature of 120°C. HBO2‐I is observed as the secondary phase when the processing temperature is 150°C. In comparison, the compacts prepared in the absence of ethanol are fragile, and the relative densities are 78.5%‐84.5% for the processing temperatures of 30‐120°C and uniaxial pressure of 500 MPa. It is indicated that ethanol promotes the densification significantly through the dissolution‐precipitation mechanism. The permittivity increases with increasing the processing temperature, while the Qf value decreases. The optimal properties with the relative density of 94.7%, εr = 4.21, Qf = 47 500 GHz, and τf = −70.0 ppm/°C were obtained in the single‐phase HBO2‐II ceramics cold sintered at 120°C under 500 MPa for 10 minutes. The relative density and Qf value are significantly higher than those of the HBO2‐II ceramic prepared by sintering the H3BO3 compact at 180°C for 2 hours (70.3% and 32 700 GHz, respectively). The results indicate that the nonaqueous solvent can also be used as the transient liquid phase for cold sintering, so that more materials that are unstable or insoluble in water can be densified by this method.
Spatial clustering, social vulnerability and risk of leprosy in an endemic area in Northeast Brazil: an ecological study
Authors: de Souza C.D.F. , Rocha V.S. , Santos N.F. , Leal T.C. , de Paiva J.P.S. , Oliveira C.C.C. , Martins‐Filho P.R.S. , Magalhães M.A.F.M. , Cuevas L.E. , Santos V.S.
Published: March 2019

Background

Despite the global decline in the detection of leprosy cases, its incidence has remained unchanged in certain settings and requires the determination of the factors linked to its persistence. We examined the spatial and space–time distribution of leprosy and the influence of social vulnerability on the occurrence of the disease in an endemic area of Northeast Brazil.

Methods

We performed an ecological study of all leprosy cases reported by Sergipe state, Northeast Brazil from 2001 to 2015, to examine the association of the Social Vulnerability Index and the prevalence and persistence of leprosy among the State's municipalities. Socio‐economic and leprosy surveillance information was collected from the Brazilian information systems, and a Bayesian empirical local model was used to identify fluctuations of the indicators. Spatial and space–time clusters were identified using scan spatial statistic tests and to measure the municipalities’ relative risk of leprosy.

Results

Leprosy clusters and burden of disease had a strong statistical association with the municipalities’ Social Vulnerability Index. Municipalities with a high social vulnerability had higher leprosy incidence, multibacillary leprosy and newly diagnosed cases with grade 2 disability than areas with low social vulnerability.

Conclusion

Social vulnerability is strongly associated with leprosy transmission and maintenance of disease incidence. Leprosy control programmes should be targeted to the populations with high social vulnerability.
Lipschütz genital ulcer revisited: is juvenile gangrenous vasculitis of the scrotum the male counterpart?
Authors: Chen W. , Plewig G.
Published: March 2019

Since its first description as ulcus vulvae acutum by Benjamin Lipschütz in 1912, the etiopathogenesis of this peculiar genital ulcer remains incompletely understood. In his original description, two different types of genital ulcers were observed and proposed, which were not precisely defined and distinguished in most subsequent reports. The first type is characterized by acute excruciating genital ulcers of first‐time onset with self‐limited non‐recurrent course in association with gravely symptomatic systemic infections, in which a primary Epstein–Barr virus (EBV) infection is later identified to be probably the most common aetiology. The second type of ulcer usually refers to little painful ulcers of unknown etiopathogenesis in the absence of fever or chills and with a slow torpid progression and recurrent nature. Differentiation from idiopathic aphthous ulcers is unclear. The changes of the cervicovaginal microbiota and microbiome in diseased state deserve further clarification. Acute genital ulcers associated with primary EBV infection in women have drawn attention since 1970s, while the corresponding penile ulcers in men were already known in 1950s. First presented in 1973, juvenile gangrenous vasculitis of the scrotum with an acute painful scrotal ulcer preceded by symptomatic pharyngeal infections can be considered as the male counterpart of ulcus vulvae acutum, and the future clinical survey should include primary EBV infection.