bluuebunny/crossref_metadata_2025_split huggingface dataset:
A cullin-RING ubiquitin ligase promotes thermotolerance as part of the Intracellular Pathogen Response in C. elegans
Authors: Panek Johan , Gang Spencer S. , Reddy Kirthi C. , Luallen Robert J. , Fulzele Amitkumar , Bennett Eric J. , Troemel Emily R. 
Published: March 2019

AbstractIntracellular pathogen infection leads to proteotoxic stress in host organisms. Previously we described a physiological program in the nematode C. elegans called the Intracellular Pathogen Response (IPR), which promotes resistance to proteotoxic stress and appears to be distinct from canonical proteostasis pathways. The IPR is controlled by PALS-22 and PALS-25, proteins of unknown biochemical function, which regulate expression of genes induced by natural intracellular pathogens. We previously showed that PALS-22 and PALS-25 regulate the mRNA expression of the predicted ubiquitin ligase component cullin cul-6, which promotes thermotolerance in pals-22 mutants. However, it was unclear whether CUL-6 acted alone, or together with other ubiquitin ligase components. Here we use co-immunoprecipitation studies paired with genetic analysis to define the cullin-RING ligase components that act together with CUL-6 to promote thermotolerance. First, we identify a previously uncharacterized RING domain protein in the TRIM family we named RCS-1, which acts as a core component with CUL-6 to promote thermotolerance. Next, we show that the Skp-related proteins SKR-3, SKR-4 and SKR-5 act redundantly to promote thermotolerance with CUL-6. Finally, we screened F-box proteins that co-immunoprecipitate with CUL-6 and find that FBXA-158 promotes thermotolerance. In summary, we have defined the three core components and an F-box adaptor of a cullin-RING ligase complex that promotes thermotolerance as part of the IPR in C. elegans, which adds to our understanding of how organisms cope with proteotoxic stress.Significance StatementIntracellular pathogen infection in the nematode Caenorhabditis elegans induces a robust transcriptional response as the host copes with infection. This response program includes several ubiquitin ligase components that are predicted to function in protein quality control. In this study, we show that these infection-induced ubiquitin ligase components form a protein complex that promotes increased tolerance of acute heat stress, an indicator of improved protein homeostasis capacity. These findings show that maintaining protein homeostasis may be a critical component of a multifaceted approach allowing the host to deal with stress caused by intracellular infection.
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

SummaryLoss 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

AbstractKinesin 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 StatementKinesins 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

IntroductionThere 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.AimIn the present review, we discuss the outcomes of the different surgical treatment modalities for neuroendocrine liver metastases.Patients and methodsA review of the published literature on the surgical management of neuroendocrine liver metastases was undertaken.ResultsLiver 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.ConclusionsHepatectomy 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

AbstractThis 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

AbstractBackgroundType 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.ObjectivesHere, we analyzed the presence of the 6mA epigenetic modification in germ cells and GCT tissues and cell lines.Materials and methodsWe 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.ResultsWe 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.DiscussionOwing 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.ConclusionIn 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

AbstractIntroductionThe aim of this systematic review was to quantify the association between birthweight discordance and neonatal morbidity in twin pregnancies.Material and methodsMEDLINE, 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.ResultsTwenty 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.ConclusionsBirthweight 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

ObjectiveTo review the mechanisms and patient outcomes for men presenting with abnormalities of the penile suspensory ligament (PSL) and their correction.Patients and MethodsWe 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.ResultsThe 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.ConclusionAbnormalities 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

AbstractIn 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

AbstractRAS 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.