bluuebunny/crossref_metadata_2025_split huggingface dataset:
Styrene maleic acid encapsulated raloxifene micelles for management of inflammatory bowel disease
Authors: Greish Khaled , Taha Safa , Jasim Anfal , Elghany Sara Abd , Sultan Ameera , AlKhateeb Ali , Othman Manal , Jun Fang , Taurin Sebastien , Bakhiet Moiz 
Published: August 2017

AbstractBackgroundInflammatory bowel disease (IBD) comprises a group of disorders that manifest through chronic inflammation of the colon and small intestine. Although the exact cause of IBD is still unclear, dysfunctional immunoregulation involving overproduction of inflammatory cytokines such as TNF‐α, and IL‐6 have been implicated in pathogenesis. Current therapy relies on immunosuppression, cytotoxic drugs, and monoclonal antibodies against TNF‐α. These classes of drugs have severe side‐effects, especially when used for long duration. Our previous work with raloxifene, a selective estrogen receptor modulator, has shown that the drug, and to a greater extent its micellar formulation, has a significant suppressive effect on NF‐κB, an essential immune‐regulator. This finding directed the current work towards testing the anti‐inflammatory and immunomodulatory effects of raloxifene using cell lines, as well as testing the potential use of the styrene maleic acid (SMA) micelles loaded with raloxifene (SMA‐Ral) against dextran sulfate sodium (DSS) induced colitis in an in vivo model of IBD.ResultsTreatment of MCF‐7 cells with TNF‐α was shown to protect the cells from the cytotoxic effect of raloxifene (42 vs. 10% cell death, with TNF‐α. Treating CaCo‐2 cells with both free and SMA‐Ral improved cell survival after exposure to 2% DDS with significantly higher protection with SMA‐Ral. Treatment of U‐937 with SMA‐Ral and free‐Ral resulted in down‐regulation of TNF‐α, IL‐1β, IL‐6, and MIP1α, with greater inhibition of the SMA‐Ral, compared to free Ral. Balb/c mice treated with raloxifene and SMA‐Ral showed weight gain at 14 days, compared to the control group (122, and 115% respectively). Treatment with raloxifene prevented DSS‐induced diarrhea in 6/6 of free raloxifene treated mice and in 5/6 mice treated with SMA‐Ral. Control group of DSS‐treated mice showed average colon length of 7.4 cm compared to 13 cm in the control group. The average colon length was 12.3 and 11.5 cm for raloxifene and SMA‐Ral treated groups, respectively. Furthermore, inflammatory cytokines such as IL‐6 and TNF‐α were reduced in serum of animals treated with free‐Ral and SMA‐Ral.ConclusionsRaloxifene and its micellar formulation warrants further studies to understand their effect on the treatment of colitis.
Uncertainty reduction through geologically conditioned petrophysical constraints in joint inversion
Authors: Giraud Jérémie , Pakyuz-Charrier Evren , Jessell Mark , Lindsay Mark , Martin Roland , Ogarko Vitaliy 
Published: August 2017

We have developed a joint geophysical inversion workflow that aims to improve subsurface imaging and decrease uncertainty by integrating petrophysical constraints and geologic data. In this framework, probabilistic geologic modeling is used as a source of information to condition the petrophysical constraints spatially and to derive starting models. The workflow then uses petrophysical measurements to constrain the values retrieved by geophysical joint inversion. The different sources of constraints are integrated into a least-squares framework to capture and integrate information related to geophysical, petrophysical, and geologic data. This allows us to quantify the posterior state of knowledge and to calculate posterior statistical indicators. To test this workflow, using geologic field data, we have generated a set of geologic models, which we used to derive a probabilistic geologic model. In this synthetic case study, we found that the integration of geologic information and petrophysical constraints in geophysical joint inversion could reduce uncertainty and improve imaging. In particular, the use of petrophysical constraints retrieves sharper boundaries and better reproduces the statistics of the observed petrophysical measurements. The integration of probabilistic geologic modeling permits more accurate retrieval of model geometry, and it better constrains the solution while still satisfying the statistics derived from geologic data. The analysis of statistical indicators at each step of the workflow indicates that (1) the inversion methodology is effective when applied to complex geology and (2) the integration of prior information and constraints from geology and petrophysics significantly improves the inversion results while decreasing uncertainty. Finally, the analysis of uncertainty to the integration of the conditioned petrophysical constraints also indicates that, for this example, the best results are obtained for joint inversion using petrophysical constraints spatially conditioned by geologic modeling.
Therapeutic strategies for spinal muscular atrophy: SMN and beyond
Authors: Bowerman Melissa , Becker Catherina G. , Yáñez-Muñoz Rafael J. , Ning Ke , Wood Matthew J. A. , Gillingwater Thomas H. , Talbot Kevin ,   The UK SMA Research Consortium
Published: August 2017

ABSTRACT
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN) due to inactivating mutations in the encoding gene SMN1. A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO) therapy has recently been licensed. However, several factors suggest that complementary strategies may be needed for the long-term maintenance of neuromuscular and other functions in SMA patients. Pre-clinical SMA models demonstrate that the requirement for SMN protein is highest when the structural connections of the neuromuscular system are being established, from late fetal life throughout infancy. Augmenting SMN may not address the slow neurodegenerative process underlying progressive functional decline beyond childhood in less severe types of SMA. Furthermore, individuals receiving SMN-based treatments may be vulnerable to delayed symptoms if rescue of the neuromuscular system is incomplete. Finally, a large number of older patients living with SMA do not fulfill the present criteria for inclusion in gene therapy and ASO clinical trials, and may not benefit from SMN-inducing treatments. Therefore, a comprehensive whole-lifespan approach to SMA therapy is required that includes both SMN-dependent and SMN-independent strategies that treat the CNS and periphery. Here, we review the range of non-SMN pathways implicated in SMA pathophysiology and discuss how various model systems can serve as valuable tools for SMA drug discovery.
Human tissue models in cancer research: looking beyond the mouse
Authors: Jackson Samuel J. , Thomas Gareth J. 
Published: August 2017

ABSTRACT
Mouse models, including patient-derived xenograft mice, are widely used to address questions in cancer research. However, there are documented flaws in these models that can result in the misrepresentation of human tumour biology and limit the suitability of the model for translational research. A coordinated effort to promote the more widespread development and use of ‘non-animal human tissue’ models could provide a clinically relevant platform for many cancer studies, maximising the opportunities presented by human tissue resources such as biobanks. A number of key factors limit the wide adoption of non-animal human tissue models in cancer research, including deficiencies in the infrastructure and the technical tools required to collect, transport, store and maintain human tissue for lab use. Another obstacle is the long-standing cultural reliance on animal models, which can make researchers resistant to change, often because of concerns about historical data compatibility and losing ground in a competitive environment while new approaches are embedded in lab practice. There are a wide range of initiatives that aim to address these issues by facilitating data sharing and promoting collaborations between organisations and researchers who work with human tissue. The importance of coordinating biobanks and introducing quality standards is gaining momentum. There is an exciting opportunity to transform cancer drug discovery by optimising the use of human tissue and reducing the reliance on potentially less predictive animal models.
Oxygen- and capacity-limited thermal tolerance: bridging ecology and physiology
Authors: Pörtner Hans-O. , Bock Christian , Mark Felix C. 
Published: August 2017

ABSTRACTObservations of climate impacts on ecosystems highlight the need for an understanding of organismal thermal ranges and their implications at the ecosystem level. Where changes in aquatic animal populations have been observed, the integrative concept of oxygen- and capacity-limited thermal tolerance (OCLTT) has successfully characterised the onset of thermal limits to performance and field abundance. The OCLTT concept addresses the molecular to whole-animal mechanisms that define thermal constraints on the capacity for oxygen supply to the organism in relation to oxygen demand. The resulting ‘total excess aerobic power budget’ supports an animal's performance (e.g. comprising motor activity, reproduction and growth) within an individual's thermal range. The aerobic power budget is often approximated through measurements of aerobic scope for activity (i.e. the maximum difference between resting and the highest exercise-induced rate of oxygen consumption), whereas most animals in the field rely on lower (i.e. routine) modes of activity. At thermal limits, OCLTT also integrates protective mechanisms that extend time-limited tolerance to temperature extremes – mechanisms such as chaperones, anaerobic metabolism and antioxidative defence. Here, we briefly summarise the OCLTT concept and update it by addressing the role of routine metabolism. We highlight potential pitfalls in applying the concept and discuss the variables measured that led to the development of OCLTT. We propose that OCLTT explains why thermal vulnerability is highest at the whole-animal level and lowest at the molecular level. We also discuss how OCLTT captures the thermal constraints on the evolution of aquatic animal life and supports an understanding of the benefits of transitioning from water to land.
Echo-acoustic scanning with noseleaf and ears in phyllostomid bats
Authors: Kugler Kathrin , Wiegrebe Lutz 
Published: August 2017

ABSTRACT
The mammalian visual system is highly directional and mammals typically employ rapid eye movements to scan their environment. Both sound emission and hearing in echolocating bats are directional but not much is known about how bats use ear movements and possibly movements of the sound-emitting structures to scan space. Here, we investigated in a tightly controlled behavioural experiment how Phyllostomus discolor bats employ their echolocation system while being moved through differently structured environments: we monitored and reconstructed both a close-up of the facial structures in 3D, including the motile noseleaf and outer ears, and the sonar-beam of the bat while it was moved along reflectors. Despite the simple linear movement of the bats in the setup, the bats pointed their beam quite variably in azimuth with a standard deviation of about ±20 deg. This variation arises from yaw-type head rotations. Video analyses show that the bat's noseleaf twitches with every echolocation call. Second, we show that the bat's ears are raised to a rather stereotypical head-centred position with every echolocation call. Surprisingly, P. discolor can adjust the timing and the magnitude of these ear movements to the distance of the reflectors with millisecond precision. Our findings reveal echolocation-specific specialisations as well as general principles of scanning and stabilisation of a directional remote sense. The call-correlated movements of the facial structures may lead to a higher directionality of the echolocation system and may enable the bats to adjust their echo-acoustic gaze to dynamic environments.
Upper lethal temperatures in three cold-tolerant insects are higher in winter than in summer
Authors: Vu Henry M. , Duman John G. 
Published: August 2017

ABSTRACT
Upper lethal temperatures (ULTs) of cold-adapted insect species in winter have not been previously examined. We anticipated that as the lower lethal temperatures (LLTs) decreased (by 20–30°C) with the onset of winter, the ULTs would also decrease accordingly. Consequently, given the recent increases in winter freeze–thaw cycles and warmer winters due to climate change, it became of interest to determine whether ambient temperatures during thaws were approaching ULTs during the cold seasons. However, beetle Dendroides canadensis (Coleoptera: Pyrochroidae) larvae had higher 24 and 48 h ULT50 (the temperature at which 50% mortality occurred) in winter than in summer. The 24 and 48 h ULT50 for D. canadensis in winter were 40.9 and 38.7°C, respectively. For D. canadensis in summer, the 24 and 48 h ULT50 were 36.7 and 36.4°C. During the transition periods of spring and autumn, the 24 h ULT50 was 37.3 and 38.5°C, respectively. While D. canadensis in winter had a 24 h LT50 range between LLT and ULT of 64°C, the summer range was only 41°C. Additionally, larvae of the beetle Cucujus clavipes clavipes (Coleoptera: Cucujidae) and the cranefly Tipula trivittata (Diptera: Tipulidae) also had higher ULTs in winter than in summer. This unexpected phenomenon of increased temperature survivorship at both lower and higher temperatures in the winter compared with that in the summer has not been previously documented. With the decreased high temperature tolerance as the season progresses from winter to summer, it was observed that environmental temperatures are closest to upper lethal temperatures in spring.
Using sheep genomes from diverse U.S. breeds to identify missense variants in genes affecting fecundity
Authors: Heaton Michael P. , Smith Timothy P.L. , Freking Bradley A. , Workman Aspen M. , Bennett Gary L. , Carnahan Jacky K. , Kalbfleisch Theodore S. 
Published: August 2017

Background: Access to sheep genome sequences significantly improves the chances of identifying genes that may influence the health, welfare, and productivity of these animals. Methods: A public, searchable DNA sequence resource for U.S. sheep was created with whole genome sequence (WGS) of 96 rams. The animals shared minimal pedigree relationships and represent nine popular U.S. breeds and a composite line. The genomes are viewable online with the user-friendly Integrated Genome Viewer environment, and may be used to identify and decode gene variants present in U.S. sheep. Results: The genomes had a combined average read depth of 16, and an average WGS genotype scoring rate and accuracy exceeding 99%. The utility of this resource was illustrated by characterizing three genes with 14 known coding variants affecting litter size in global sheep populations: growth and differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15), and bone morphogenetic protein receptor 1B (BMPR1B). In the 96 U.S. rams, nine missense variants encoding 11 protein variants were identified. However, only one was previously reported to affect litter size (GDF9 V371M, Finnsheep). Two missense variants in BMP15 were identified that had not previously been reported: R67Q in Dorset, and L252P in Dorper and White Dorper breeds. Also, two novel missense variants were identified in BMPR1B: M64I in Katahdin, and T345N in Romanov and Finnsheep breeds. Based on the strict conservation of amino acid residues across placental mammals, the four variants encoded by BMP15 and BMPR1B are predicted to interfere with their function. However, preliminary analyses of litter sizes in small samples did not reveal a correlation with variants in BMP15 and BMPR1B with daughters of these rams. Conclusions: Collectively, this report describes a new resource for discovering protein variants in silico and identifies alleles for further testing of their effects on litter size in U.S. breeds.
Technical Note—Dynamic Pricing and Demand Learning with Limited Price Experimentation
Authors: Cheung Wang Chi , Simchi-Levi David , Wang He 
Published: August 2017

In a dynamic pricing problem where the demand function is not known a priori, price experimentation can be used as a demand learning tool. Existing literature usually assumes no constraint on price changes, but in practice, sellers often face business constraints that prevent them from conducting extensive experimentation. We consider a dynamic pricing model where the demand function is unknown but belongs to a known finite set. The seller is allowed to make at most m price changes during T periods. The objective is to minimize the worst-case regret—i.e., the expected total revenue loss compared with a clairvoyant who knows the demand distribution in advance. We demonstrate a pricing policy that incurs a regret of O(log(m) T), or m iterations of the logarithm. Furthermore, we describe an implementation of this pricing policy at Groupon, a large e-commerce marketplace for daily deals. The field study shows significant impact on revenue and bookings. The e-companion is available at https://doi.org/10.1287/opre.2017.1629 .
Screening Strategies for Patients on the Kidney Transplant Waiting List
Authors: Sabouri Alireza , Huh Woonghee Tim , Shechter Steven M. 
Published: August 2017

Transplant centers screen patients on the kidney transplant waiting list to identify patients with severe conditions such as cardiovascular disease (CVD), which makes them ineligible for a transplant. We propose a model for finding screening strategies, with the objective of minimizing the sum of the expected screening cost and the expected penalty cost associated with transplanting an organ to an ineligible patient. Our results suggest that current screening guidelines, which are based only on patients’ risk for developing CVD, are significantly dominated by policies that also consider factors related to patients’ waiting time. In particular, our numerical experiments based on waiting list data in British Columbia show that compared with the current screening policy, our model-based policy results in a 35.6% reduction in the total annual cost by reducing the percentage of kidneys offered to patients with undetected CVD by 57.4% while using only 5% more screenings per year. The online appendix is available at https://doi.org/10.1287/opre.2017.1632 .
Consenting to sexual activity
Authors: Griffith Richard 
Published: August 2017

Engaging in sexual activity is an essential Human Right protected under article 12 of the European Convention on Human Rights ( Council of Europe, 1950 ) and should be free from state interference. District nurses, however, often express concern over the possibility that adults with acquired brain injury or a learning disability cannot give a real consent to participate in sexual activity and so should be prevented from doing so. In this article Richard Griffith reviews the case law in relation to the capacity to consent to sexual activity.
Anterior cruciate ligament reconstruction in skeletally immature patients
Authors: Longo U. G. , Ciuffreda M. , Casciaro C. , Mannering N. , Candela V. , Salvatore G. , Denaro V. 
Published: August 2017

Aims Different methods of anterior cruciate ligament (ACL) reconstruction have been described for skeletally immature patients before closure of the growth plates. However, the outcome and complications following this treatment remain unclear. The aim of this systematic review was to analyse the outcome and complications of different techniques which may be used for reconstruction of the ACL in these patients. Materials and Methods We performed a systematic review of the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. This involved a comprehensive search of PubMed, Medline, CINAHL, Cochrane, Embase and Google Scholar databases using the following combinations of keywords, “knee”, “anterior cruciate ligament”, “reconstruction”, “injury”, “children”, “adolescent”, “skeletally immature”, “open physis” and “surgery”. Results A total of 53 studies met the inclusion criteria and were included for analysis. The overall rate of disturbance of growth after ACL reconstruction was 2.6%, with no statistical difference between transphyseal and physeal-sparing techniques. Physeal-sparing techniques had a lower rate of post-operative complications compared with transphyseal techniques (p = 0.0045). Outcomes assessed were Lysholm score, International Knee Documentation Committee (IKDC) score, the IKDC grade, the Tegner score and the KT-1000. Both techniques had similar clinical outcomes. Conclusions This review reveals low rates of disturbance of growth after ACL reconstruction in skeletally immature patients. Although limited, the available evidence did not support any particular surgical technique when considering disturbance of growth or clinical outcome. Further randomised controlled trials are needed to investigate the efficacy of differing surgical techniques on outcomes in skeletally immature patients. Cite this article: Bone Joint J 2017;99-B:1053–60.
Plate fixationversusintramedullary nailing of completely displaced midshaft fractures of the clavicle
Authors: Fuglesang H. F. S. , Flugsrud G. B. , Randsborg P. H. , Oord P. , Benth J. Š. , Utvåg S. E. 
Published: August 2017

AimsThis is a prospective randomised controlled trial comparing the functional outcomes of plate fixation and elastic stable intramedullary nailing (ESIN) of completely displaced mid-shaft fractures of the clavicle in the active adult population.Patients and MethodsWe prospectively recruited 123 patients and randomised them to either plate fixation or ESIN. Patients completed the Quick Disabilities of the Arm, Shoulder and Hand (DASH) score at one to six weeks post-operatively. They were followed up at six weeks, three and six months and one year with radiographs, and their clinical outcome was assessed using both the DASH and the Constant Score.ResultsPlate fixation provided a faster functional recovery during the first six months compared with ESIN, but there was no difference after one year. The duration of surgery was shorter for ESIN (mean 53.4 minutes, 22 to 120) than for plate fixation (mean 69.7 minutes, 35 to 106, p < 0.001). The recovery after ESIN was slower with increasing fracture comminution and with open reduction (p < 0.05).ConclusionBoth methods return the patients to their pre-injury functional levels, but plate fixation has a faster recovery period in comminuted fractures than ESIN. ESIN has a shorter operative time and lower infection and implant rates of failure when using 2.5 mm nails or wider, suggesting that this is the preferred method in mid-shaft fractures with no comminution, whereas plate fixation is the superior method in comminuted fractures. Cite this article: Bone Joint J 2017;99-B:1095–1101
The use of highly crosslinked polyethylene in total knee arthroplasty
Authors: Brown T. S. , Van Citters D. W. , Berry D. J. , Abdel M. P. 
Published: August 2017

Advances in polyethylene (PE) in total hip arthroplasty have led to interest and increased use of highly crosslinked PE (HXLPE) in total knee arthroplasty (TKA). Biomechanical data suggest improved wear characteristics for HXLPE inserts over conventional PE in TKA. Short-term results from registry data and few clinical trials are promising. Our aim is to present a review of the history of HXLPEs, the use of HXLPE inserts in TKA, concerns regarding potential mechanical complications, and a thorough review of the available biomechanical and clinical data.Cite this article: Bone Joint J 2017;99-B:996–1002.