bluuebunny/crossref_metadata_2025_split huggingface dataset:
Haploid Mammalian Genetic Screen Identifies UBXD8 as a Key Determinant of HMGCR Degradation and Cholesterol Biosynthesis
Authors: Loregger Anke , Raaben Matthijs , Tan Josephine , Scheij Saskia , Moeton Martina , van den Berg Marlene , Gelberg-Etel Hila , Stickel Elmer , Roitelman Joseph , Brummelkamp Thijn , Zelcer Noam 
Published: September 2017

Objective—
The cellular demand for cholesterol requires control of its biosynthesis by the mevalonate pathway. Regulation of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase), a rate-limiting enzyme in this pathway and the target of statins, is a key control point herein. Accordingly, HMGCR is subject to negative and positive regulation. In particular, the ability of oxysterols and intermediates of the mevalonate pathway to stimulate its proteasomal degradation is an exquisite example of metabolically controlled feedback regulation. To define the genetic determinants that govern this process, we conducted an unbiased haploid mammalian genetic screen.

Approach and Results—
We generated human haploid cells with mNeon fused to endogenous HMGCR using CRISPR/Cas9 and used these cells to interrogate regulation of HMGCR abundance in live cells. This resulted in identification of known and new regulators of HMGCR, and among the latter, UBXD8 (ubiquitin regulatory X domain-containing protein 8), a gene that has not been previously implicated in this process. We demonstrate that UBXD8 is an essential determinant of metabolically stimulated degradation of HMGCR and of cholesterol biosynthesis in multiple cell types. Accordingly, UBXD8 ablation leads to aberrant cholesterol synthesis due to loss of feedback control. Mechanistically, we show that UBXD8 is necessary for sterol-stimulated dislocation of ubiquitylated HMGCR from the endoplasmic reticulum membrane en route to proteasomal degradation, a function dependent on its UBX domain.

Conclusions—
We establish UBXD8 as a previously unrecognized determinant that couples flux across the mevalonate pathway to control of cholesterol synthesis and demonstrate the feasibility of applying mammalian haploid genetics to study metabolic traits.
Formation and Dynamics of a Long-Lived Eddy Train in the South China Sea: A Modeling Study
Authors: Cai Zhongya , Gan Jianping 
Published: September 2017

AbstractA process-oriented numerical modeling study was conducted to investigate the formation and underlying forcing of an anticyclonic eddy train observed in the northern South China Sea. Observations showed that long-lived anticyclonic eddies formed an eddy train along an eastward separated jet across the northern South China Sea in summer. The eddy train plays a critical role in regulating ocean circulation in the region. Forced by the southwesterly monsoon and prevailing dipole wind stress curl in the summer, the northward coastal jet separates from the west boundary of the South China Sea basin and overshoots northeastward into the basin. The anticyclonic recirculation of the separated jet forms the first anticyclonic eddy in the eddy train. The jet meanders downstream with a strong negative shear vorticity that forms a second and a third anticyclonic eddy along the jet’s path. These three eddies form the eddy train. These eddies weaken gradually with depth from surface, but they can extend to approximately 500 m deep. The inherent stratification in the region regulates the three-dimensional scale of the anticyclonic eddies and constrains their intensity vertical extension by weakening the geostrophic balance within these eddies. Analyses of the vorticity balance indicate that the eddy train’s negative vorticity originates from the beta effect of northward western boundary current and from the subsequent downstream vorticity advection in the jet. The jet separation is a necessary condition for the formation of the eddy train, and the enhanced stratification, increased summer wind stress, and associated negative wind stress curl are favorable conditions for the formation of the anticyclonic eddies.
Assessing the Relationship between Disordered Gamblers with Psychosis and Increased Gambling Severity: The Mediating Role of Impulsivity
Authors: Kim Hyoun S. , Cassetta Briana D. , Hodgins David C. , Tomfohr-Madsen Lianne M. , McGrath Daniel S. , Tavares Hermano 
Published: September 2017

Objective: Recent research suggests that disordered gambling and psychosis co-occur at higher rates than expected in the general population. Gamblers with psychosis also report greater psychological distress and increased gambling severity. However, the mechanism by which psychosis leads to greater gambling symptomology remains unknown. The objective of the present research was to test whether impulsivity mediated the relationship between comorbid psychosis and gambling severity. Method: The sample consisted of 394 disordered gamblers voluntarily seeking treatment at a large university hospital in São Paulo, Brazil. A semistructured clinical interview (Mini-International Neuropsychiatric Interview) was used to diagnosis the presence of psychosis by registered psychiatrists. Severity of gambling symptoms was assessed using the Gambling Symptom Assessment Scale, and the Barratt Impulsiveness Scale–11 provided a measure of impulsivity. Results: Of the sample, 7.2% met diagnostic criteria for psychosis. Individuals with a dual diagnosis of psychosis did not report greater gambling severity. Conversely, dual diagnoses of psychosis were associated with greater levels of impulsivity. Higher levels of impulsivity were also associated with greater gambling severity. Importantly, support for our hypothesised mediation model was found such that impulsivity mediated the association between disordered gambling and psychosis and gambling severity. Conclusion: Impulsivity appears to be a transdiagnostic process that may be targeted in treatment among disordered gamblers with a dual diagnosis of psychosis to reduce problematic gambling behaviours.
Predictors of Change in Quality of Life in Patients With End-Stage Disease During Hospitalization
Authors: Bužgová Radka , Sikorová Lucie , Kozáková Radka , Jarošová Darja 
Published: September 2017

Background: Currently, there are no studies aimed at evaluating the quality of life (QoL) of patients with end-stage disease during hospitalization and the factors that influence it. Aim: The aim of the research was to identify predictors of change in the QoL of patients hospitalized due to advanced stage of disease. Methods: The sample consisted of 140 patients with end-stage disease who were hospitalized on this account. For evaluation of QoL, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was used. The Hospital Anxiety and Depression Scale and Karnofsky Performance Status questionnaires were used for the assessment of mental and functional status. For the evaluation of predictors of negative change in QoL, a logistic regression analysis was used. Results: During hospitalization, there was a significant deterioration in the scores given for all domains of the functional QLQ-C30 scale, but not the symptomatic scale. Predictors of change in overall QoL detected were marital status, improved functional status, and depression detected on admission to hospital. Gender and age were found to be protective factors against deterioration in overall QoL. Conclusion: Sociodemographic characteristics and mental and functional status may be associated with change in QoL of patients with end-stage disease during hospitalization.
Effect of Sequential Sectioning of Ligaments on Syndesmotic Instability in the Coronal Plane Evaluated Arthroscopically
Authors: Massri-Pugin Jafet , Lubberts Bart , Vopat Bryan G. , Guss Daniel , Hosseini Ali , DiGiovanni Christopher W. 
Published: September 2017

Background: Arthroscopic evaluation of the syndesmosis allows direct visualization of syndesmotic instability. The purpose of this study was to determine the minimum degree of ligamentous injury necessary to destabilize the syndesmosis in the coronal plane when assessed arthroscopically and pinpoint where such instability should be measured within the incisura. Methods: Fourteen cadaveric specimens were divided into 2 groups and arthroscopically assessed first with the syndesmosis intact and then following serial differential ligamentous transection. Group 1 (n = 7): anterior-inferior tibiofibular (AITFL), interosseous (IOL), posterior-inferior tibiofibular (PITFL), and deltoid (DL) ligament. Group 2 (n = 7): PITFL-IOL-AITFL-DL. At each step, a standard 100-N lateral hook test was applied and tibiofibular coronal plane diastasis measured arthroscopically at both the anterior and posterior third of the incisura. These measurements were in turn compared with those of the stressed intact ligamentous state. Results: There was no significant syndesmotic instability measured at either the anterior or posterior margin of the incisura after transection of a singular ligament (AITFL or PITFL) or after the IOL was additionally transected. Diastasis at the posterior margin was significantly increased when all syndesmotic ligaments were sectioned (group 1: P = .018; group 2: P = .008), but this was not noted along the anterior margin. Diastasis at the anterior margin reached significance only with complete transection of syndesmosis and DL (group 1: P < .001; group 2: P = .044). Conclusion: Under arthroscopic evaluation, the syndesmosis becomes unstable in the coronal plane only when all syndesmotic ligaments are transected, which should preferentially be measured at the posterior margin of the incisura. Anteriorly, diastasis becomes apparent only with addition of DL disruption, although this added finding may aid in diagnosis of occult deltoid injury. Clinical Relevance: AITFL, IOL, and PITFL need to be injured to produce coronal plane syndesmotic instability. Arthroscopic assessment of such instability should occur along the posterior margin of the incisura. When they exist, similar findings anteriorly suggest concomitant deltoid injury.
Ex Vivo and In Vivo Noninvasive Imaging of Epidermal Growth Factor Receptor Inhibition on Colon Tumorigenesis Using Activatable Near-Infrared Fluorescent Probes
Authors: Ding Shengli , Blue Randall E. , Moorefield Emily , Yuan Hong , Lund Pauline K. 
Published: September 2017

Background: Near-infrared fluorescence (NIRF) imaging combined with enzyme-activatable NIRF probes has yielded promising results in cancer detection. Objective: To test whether 3-dimensional (3-D) noninvasive in vivo NIRF imaging can detect effects of epidermal growth factor receptor (EGFR) inhibitor on both polypoid and flat tumor load in azoxymethane (AOM)-induced colon tumors or tumors in ApcMin/+ mice. Methods: The AOM-injected KK-HIJ mice received EGFR inhibitor diet or chow diet. These and ApcMin/+ mice were given cathepsin-activatable probes (ProSense 680) before imaging. In vivo imaging was performed using quantitative tomographic NIRF imaging. Ex vivo imaging and histologic examination were performed. Dual imaging by micro computed tomography (CT) and 3D NIRF imaging was used to verify tumor location. Results: Tumor load reduction by EGFR inhibition was detected ex vivo using cathepsin B probes. In vivo imaging revealed intense activation of probes only in large tumors. Dual imaging with microCT and 3D NIRF imaging improved tumor detection in vivo. Conclusions: The 3-D NIRF imaging with ProSense 680 can detect and quantify drug effects on colon tumors ex vivo. The NIRF imaging with ProSense 680 probe has limitations as a valid nonendoscopic method for intestinal tumor detection. Combing with other imaging modalities will improve the specificity and sensitivity of intestinal tumor detection in vivo.
Success in national level junior tennis: Tactical perspectives
Authors: Klaus Anne , Bradshaw Ryan , Young Warren , O’Brien Brendan , Zois James 
Published: September 2017

Purpose Point duration in competitive tennis is becoming shorter, highlighting a greater emphasis on performance of the first strokes of each point, in particular, the performance of the server. Methods Descriptive measures of the video-based analysis included stroke type, point outcome and stroke position of the first two strokes of the server (service and first shot) during 10 randomly selected sets of competition on hard court. All participants (male; n = 8) were of the age group 14 years and below and competed in national level events. Results The performance of the first serve is characterized by an “in-percentage” of 54.6% and an improved chance of winning the point (for the server) following a first serve (55.9%; P < 0.001) compared to a second serve (42.9%). The majority of stroke positions for first-shot winners were located in the central zone of the court (52.1%; P < 0.01). In comparison to the error rate of all examined strokes, we observed an increased error rate of the first shot (16.5% vs. 22.4%; P < 0.01). Conclusion Contrasting to professionals, juniors produce more first-serve errors and win fewer points directly via the serve. Success in junior tennis relies in minimizing errors within short rallies specifically on the first shot of the server. Coaches of national level junior tennis players should focus on strategies to optimize court position following the serve and service percentage to increase competitive success rate. To achieve this, the server should utilize the serve as a “set-up” tool, dictating the direction of the returner’s return of serve within the central zones of the court.
Changes in Insurance Coverage and Stage at Diagnosis Among Nonelderly Patients With Cancer After the Affordable Care Act
Authors: Jemal Ahmedin , Lin Chun Chieh , Davidoff Amy J. , Han Xuesong 
Published: September 2017

Purpose To examine change in the percent uninsured and early-stage diagnosis among nonelderly patients with newly diagnosed cancer after the Affordable Care Act (ACA). Patients and Methods By using the National Cancer Data Base, we estimated absolute change (APC) and relative change in percent uninsured among patients with newly diagnosed cancer age 18 to 64 years between 2011 to the third quarter of 2013 (pre-ACA implementation) and the second to fourth quarter of 2014 (post-ACA) in Medicaid expansion and nonexpansion states by family income level. We also examined demographics-adjusted difference in differences in APC between Medicaid expansion and nonexpansion states. We similarly examined changes in insurance and early-stage diagnosis for the 15 leading cancers in men and women (top 17 cancers total). Results Between the pre-ACA and post-ACA periods, percent uninsured among patients with newly diagnosed cancer decreased in all income categories in both Medicaid expansion and nonexpansion states. However, the decrease was largest in low-income patients who resided in expansion states (9.6% to 3.6%; APC, −6.0%; 95% CI, −6.5% to −5.5%) versus their counterparts who resided in nonexpansion states (14.7% to 13.3%; APC, −1.4%; 95% CI, −2.0% to −0.7%), with an adjusted difference in differences of −3.3 (95% CI, −4.0 to −2.5). By cancer type, the largest decrease in percent uninsured occurred in patients with smoking- or infection-related cancers. A small but statistically significant shift was found toward early-stage diagnosis for colorectal, lung, female breast, and pancreatic cancer and melanoma in patients who resided in expansion states. Conclusion Percent uninsured among nonelderly patients with newly diagnosed cancer declined substantially after the ACA, especially among low-income people who resided in Medicaid expansion states. A trend toward early-stage diagnosis for select cancers in expansion states also was found. These results reinforce the importance of policies directed at providing affordable coverage to low-income, vulnerable populations.
Leverage of an Existing Cervical Cancer Prevention Service Platform to Initiate Breast Cancer Control Services in Zambia: Experiences and Early Outcomes
Authors: Pinder Leeya F. , Henry-Tillman Ronda , Linyama David , Kusweje Victor , Nzayisenga Jean-Baptiste , Shibemba Aaron , Sahasrabuddhe Vikrant , Lishimpi Kennedy , Mwanahamuntu Mulindi , Hicks Michael , Parham Groesbeck P. 
Published: September 2017

Purpose In 2005, the Cervical Cancer Prevention Program in Zambia (CCPPZ) was implemented and has since provided cervical cancer screen-and-treat services to more than 500,000 women. By leveraging the successes and experiences of the CCPPZ, we intended to build capacity for the early detection and surgical treatment of breast cancer. Methods Our initiative sought to build capacity for breast cancer care through the (1) formation of a breast cancer advocacy alliance to raise awareness, (2) creation of resource-appropriate breast cancer care training curricula for mid- and high-level providers, and (3) implementation of early detection and treatment capacity within two major health care facilities. Results Six months after the completion of the initiative, the following outcomes were documented: Breast health education and clinical breast examination (CBE) services were successfully integrated into the service platforms of four CCPPZ clinics. Two new breast diagnostic centers were opened, which provided access to breast ultrasound, ultrasound-guided core needle biopsy, and needle aspiration. Breast health education and CBE were provided to 1,955 clients, 167 of whom were evaluated at the two diagnostic centers; 55 of those evaluated underwent core-needle biopsy, of which 17 were diagnosed with invasive cancer. Newly trained surgeons performed six sentinel lymph node mappings, eight sentinel lymph node dissections, and 10 breast conservation surgeries (lumpectomies). Conclusion This initiative successfully established clinical services in Zambia that are critical for the early detection and surgical management of breast cancer.
Integrin α8 and Pcdh15 act as a complex to regulate cilia biogenesis in sensory cells
Authors: Goodman Linda , Zallocchi Marisa 
Published: September 2017

ABSTRACT
The way an organism perceives its surroundings depends on sensory systems and the highly specialized cilia present in the neurosensory cells. Here, we describe the existence of an integrin α8 (Itga8) and protocadherin-15a (Pcdh15a) ciliary complex in neuromast hair cells in a zebrafish model. Depletion of the complex via downregulation or loss-of-function mutation leads to a dysregulation of cilia biogenesis and endocytosis. At the molecular level, removal of the complex blocks the access of Rab8a into the cilia as well as normal recruitment of ciliary cargo by centriolar satellites. These defects can be reversed by the introduction of a constitutively active form of Rhoa, suggesting that Itga8–Pcdh15a complex mediates its effect through the activation of this small GTPase and probably by the regulation of actin cytoskeleton dynamics. Our data points to a novel mechanism involved in the regulation of sensory cilia development, with the corresponding implications for normal sensory function.
Lipopolysaccharide modulates p300 and Sirt1 to promote PRMT1 stability via an SCFFbxl17-recognized acetyldegron
Authors: Lai Yandong , Li Jin , Li Xiuying , Zou Chunbin 
Published: September 2017

ABSTRACT
E3 ubiquitin ligase recognizes its protein substrates via specific molecular signatures for ubiquitin proteasomal degradation. However, the role of acetylation/deacetylation in the process of E3 ubiquitin ligase recognizing its protein substrates is not fully studied. Here, we report that a tandem IK motif in protein arginine methyltransferase 1 (PRMT1) forms an acetyldegron to recruit the F-box/LRR-repeat protein 17 (FBXL17), a component of the SKP1–CUL1–F-box protein (SCF)-type E3 ubiquitin ligase complex. PRMT1 is polyubiquitylated for proteasome degradation with a half-life of approximately 4 h in lung epithelial cells. SCFFbxl17 mediates PRMT1 polyubiquitylation at K117. SCFFbxl17 specifically binds PRMT1 via a unique motif IKxxxIK. Strikingly, the acetylation/deacetylation status of the lysine residues within the motif determines Fbxl17 binding. Deacetylation on both K200 and K205 by Sirtuin 1 (Sirt1) and acetylation of p300 (EP300) on K205 collaboratively prepare the motif for SCFFbxl17 binding thereby triggering PRMT1 protein degradation. Pathogen-derived lipopolysaccharide (LPS) downregulates Sirt1 and p300 to protect PRMT1 from degradation. This study demonstrates that LPS promotes PRMT1 stability by blockade of PRMT1 and SCFFbxl17 binding via an acetylation/deacetylation-modified acetyldegron; and LPS-elevated levels of PRMT1 lead to bronchial epithelial cell overgrowth in pulmonary inflammatory diseases.
COG7 deficiency in Drosophila generates multifaceted developmental, behavioral and protein glycosylation phenotypes
Authors: Frappaolo Anna , Sechi Stefano , Kumagai Tadahiro , Robinson Sarah , Fraschini Roberta , Karimpour-Ghahnavieh Angela , Belloni Giorgio , Piergentili Roberto , Tiemeyer Katherine H. , Tiemeyer Michael , Giansanti Maria Grazia 
Published: September 2017

ABSTRACT
Congenital disorders of glycosylation (CDG) comprise a family of human multisystemic diseases caused by recessive mutations in genes required for protein N-glycosylation. More than 100 distinct forms of CDGs have been identified and most of them cause severe neurological impairment. The Conserved Oligomeric Golgi (COG) complex mediates tethering of vesicles carrying glycosylation enzymes across the Golgi cisternae. Mutations affecting human COG1, COG2 and COG4–COG8 cause monogenic forms of inherited, autosomal recessive CDGs. We have generated a Drosophila COG7-CDG model that closely parallels the pathological characteristics of COG7-CDG patients, including pronounced neuromotor defects associated with altered N-glycome profiles. Consistent with these alterations, larval neuromuscular junctions of Cog7 mutants exhibit a significant reduction in bouton numbers. We demonstrate that the COG complex cooperates with Rab1 and Golgi phosphoprotein 3 to regulate Golgi trafficking and that overexpression of Rab1 can rescue the cytokinesis and locomotor defects associated with loss of Cog7. Our results suggest that the Drosophila COG7-CDG model can be used to test novel potential therapeutic strategies by modulating trafficking pathways.
Achieving prescribing competencies
Authors: Lowery-Brady Hannah 
Published: September 2017

To gain the independent and supplementary prescribing qualification, it is essential to meet the competencies within the ‘Single Competency Framework’ for prescribers and the professional standards set out by the Nursing and Midwifery Council (NMC). The NMC are currently reviewing the ‘Standards of Proficiency for Nurse and Midwife Prescribers’ and are looking to move to using the Royal Pharmaceutical Society's ‘Single Competency Framework’. There is limited literature and guidance available to support the use of the competencies for prescribing. Relevant sources of information that were found useful for assisting prescribing practice have been identified. Reflections on how each competency has been achieved and how this has been evidenced are discussed. This includes reflective practice, supervised practice and case studies, which are identified as essential for achieving competence in prescribing.