bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lessons from LIMK1 enzymology and their impact on inhibitor design
Authors: Salah Eidarus , Chatterjee Deep , Beltrami Alessandra , Tumber Anthony , Preuss Franziska , Canning Peter , Chaikuad Apirat , Knaus Petra , Knapp Stefan , Bullock Alex N. , Mathea Sebastian 
Published: October 2019

Abstract
LIM domain kinase 1 (LIMK1) is a key regulator of actin dynamics. It is thereby a potential therapeutic target for the prevention of fragile X syndrome and amyotrophic lateral sclerosis. Herein, we use X-ray crystallography and activity assays to describe how LIMK1 accomplishes substrate specificity, to suggest a unique ‘rock-and-poke’ mechanism of catalysis and to explore the regulation of the kinase by activation loop phosphorylation. Based on these findings, a differential scanning fluorimetry assay and a RapidFire mass spectrometry activity assay were established, leading to the discovery and confirmation of a set of small-molecule LIMK1 inhibitors. Interestingly, several of the inhibitors were inactive towards the closely related isoform LIMK2. Finally, crystal structures of the LIMK1 kinase domain in complex with inhibitors (PF-477736 and staurosporine, respectively) are presented, providing insights into LIMK1 plasticity upon inhibitor binding.
Phosphoproteomics reveals that the hVPS34 regulated SGK3 kinase specifically phosphorylates endosomal proteins including Syntaxin-7, Syntaxin-12, RFIP4 and WDR44
Authors: Malik Nazma , Nirujogi Raja S. , Peltier Julien , Macartney Thomas , Wightman Melanie , Prescott Alan R. , Gourlay Robert , Trost Matthias , Alessi Dario R. , Karapetsas Athanasios 
Published: October 2019

Abstract
The serum- and glucocorticoid-regulated kinase (SGK) isoforms contribute resistance to cancer therapies targeting the PI3K pathway. SGKs are homologous to Akt and these kinases display overlapping specificity and phosphorylate several substrates at the same residues, such as TSC2 to promote tumor growth by switching on the mTORC1 pathway. The SGK3 isoform is up-regulated in breast cancer cells treated with PI3K or Akt inhibitors and recruited and activated at endosomes, through its phox homology domain binding to PtdIns(3)P. We undertook genetic and pharmacological phosphoproteomic screens to uncover novel SGK3 substrates. We identified 40 potential novel SGK3 substrates, including four endosomal proteins STX7 (Ser126) and STX12 (Ser139), RFIP4 (Ser527) and WDR44 (Ser346) that were efficiently phosphorylated in vitro by SGK3 at the sites identified in vivo, but poorly by Akt. We demonstrate that these substrates are inefficiently phosphorylated by Akt as they possess an n + 1 residue from the phosphorylation site that is unfavorable for Akt phosphorylation. Phos-tag analysis revealed that stimulation of HEK293 cells with IGF1 to activate SGK3, promoted phosphorylation of a significant fraction of endogenous STX7 and STX12, in a manner that was blocked by knock-out of SGK3 or treatment with a pan SGK inhibitor (14H). SGK3 phosphorylation of STX12 enhanced interaction with the VAMP4/VTI1A/STX6 containing the SNARE complex and promoted plasma membrane localization. Our data reveal novel substrates for SGK3 and suggest a mechanism by which STX7 and STX12 SNARE complexes are regulated by SGK3. They reveal new biomarkers for monitoring SGK3 pathway activity.
BAP1 promotes stalled fork restart and cell survival via INO80 in response to replication stress
Authors: Lee Han-Sae , Seo Hye-Ran , Lee Shin-Ai , Choi Soohee , Kang Dongmin , Kwon Jongbum 
Published: October 2019

Abstract
The recovery from replication stress by restarting stalled forks to continue DNA synthesis is crucial for maintaining genome stability and thereby preventing diseases such as cancer. We previously showed that BRCA1-associated protein 1 (BAP1), a nuclear deubiquitinase with tumor suppressor activity, promotes replication fork progression by stabilizing the INO80 chromatin remodeler via deubiquitination and recruiting it to replication forks during normal DNA synthesis. However, whether BAP1 functions in DNA replication under stress conditions is unknown. Here, we show that BAP1 depletion reduces S-phase progression and DNA synthesis after treatment with hydroxyurea (HU). BAP1-depleted cells exhibit a defect in the restart of HU-induced stalled replication forks, which is recovered by the ectopic expression of INO80. Both BAP1 and INO80 bind chromatin at replication forks upon HU treatment. BAP1 depletion abrogates the binding of INO80 to replication forks and increases the formation of RAD51 foci following HU treatment. BAP1-depleted cells show hypersensitivity to HU treatment, which is rescued by INO80 expression. These results suggest that BAP1 promotes the restart of stress-induced stalled replication forks by recruiting INO80 to the stalled forks. This function of BAP1 in replication stress recovery may contribute to its ability to suppress genome instability and cancer development.
Specific panallergen peptide of Sorghum Polcalcin showing IgE response identified based on in silico and in vivo peptide mapping
Authors: Bokka Chandra Sekhar , Veeramachaneni Ganesh Kumar , Thunuguntla V.B.S.C. , Manda Naresh Kumar , Bondili Jayakumar Singh 
Published: October 2019

Abstract
In India, Sorghum plant allergenicity was reported to be approximately 54.9%. Sorghum bicolor Polcalcin (Sorb PC) was identified as the panallergen but the specificity of this allergen is yet to be characterized. The present study was aimed to characterize the antigenic determinants of Sorb PC that are responsible for eliciting the IgE response. In silico modeling, simulation studies and docking of Sorb PC peptides (PC1–11) against IgG and IgE followed by in vivo evaluation was adopted. Peptide docking studies revealed PC 6 with highest G-score −12.85 against IgE followed by PC-11, 5, 1 and 7 (−10.91) peptides. The mice sensitized with PC7 peptide showed interleukin (IL) 4 (IL-4), IL-5, IL-12, TNF-α and GMCSF levels increased when compared with other peptides and controls, signifying a strong T helper type 2 (Th2)-based response. In tandem, the T helper type 1 (Th1) pathway was inhibited by low levels of cytokine IL-2, interferon γ (IFN-γ) and increased IL-10 levels justifying the role of PC7 in allergic IgE response. Considering the above data of overlapping peptides of PC6 and PC7, N-terminal part of the PC7 peptide (DEVQRMM) is found to play a crucial role in Sorghum Polcalcin allergenic response.
Wie gut sind Ältere in Deutschland mit essenziellen Nährstoffen versorgt?
Authors: Eggersdorfer Manfred 
Published: October 2019

ZusammenfassungDie Versorgung mit essenziellen Mikronährstoffen, also Vitaminen und Mineralstoffen, ist für ein gesundes Leben und Altern von großer Bedeutung. Der Nutzen eines optimalen Nährstoffstatus für ein gesundes Leben und Altern zeigt sich bei der Mobilität im Alter aufgrund von guter Muskelstärke und Knochendichte, der Augengesundheit durch eine gute optische Makulapigmentdichte, der Aufrechterhaltung der kognitiven Funktion, gute Herzgesundheit durch Blutdruck- und Triglyceridmanagement und der Stärkung des Immunsystems.
School Bag Packs and Associated Problems among School Going Children
Authors: Hassan Danish , Kashif Muhammad , Bandpei Mohammad A.Mohseni , Ali Summiya Qudrat , Raqib Abdul , Manzoor Nosheen , Zahid Saima , Rafiullah Ahmed 
Published: October 2019

Abstract
Objective The objective of this study was to assess school backpacks and associated problems across school going children aged 8–12 years in Lahore, Pakistan. Self-perceived pain related to bag pack use, correlation between self-reported pain and perceived weight of bag pack, duration of bag pack carriage and the method of bag pack carriage were evaluated.
Methodology A cross-sectional survey was conducted on 3500 students from different private schools across Lahore. Both male and female students from the age of 8–12 years that were present on the day of the study with no apparent physical deformity or any musculoskeletal disorder were included in the study. Questionnaire used in this study was a modified questionnaire from a previous study.Data collected through questionnaire was coded into SPSS version 18.Data was represented in the form of graphs, tables, cross tabs and bar charts. Chi square test of association was applied with p value<0.05 considered as significant.
Results The results indicate that 82% of students surveyed carry bag packs, 54.66% of the students perceived the weight of their bag pack heavy, 40.22% medium while only 5.12% reported their bag pack lightly weighed. Pain was higher in individuals who perceived their bag pack weight heavy (i. e., 48%) pain, who carried their bag pack for over 20 min (44%) pain and over 30 min (56%) pain, respectively. Similarly percentage of pain was higher in individuals who carried their bag pack at one shoulder (i. e., 74%) pain.
Conclusion The results of the present study show that there is a relationship between bag pack use, duration and method of bag pack carriage this suggests that heavy, medium and light bag packs may have damaging effects for the school going children. A study to compare children who follow and that do not follow the recommended guidelines should be conducted to find out the guidelines could help reduce back pain, the bag pack guidelines have addressed bag pack weight and duration of carriage should be considered.
Development and Characterization of the Neuroregenerative Xanthohumol C/Hydroxypropyl-β-cyclodextrin Complex Suitable for Parenteral Administration
Authors: Kirchinger Michael , Bieler Lara , Tevini Julia , Vogl Michael , Haschke-Becher Elisabeth , Felder Thomas K. , Couillard-Després Sebastien , Riepl Herbert , Urmann Corinna 
Published: October 2019

AbstractThe chroman-like chalcone Xanthohumol C, originally found in hops, was demonstrated to be a potent neuroregenerative and neuroprotective natural product and therefore constitutes a strong candidate for further pharmaceutical research. The bottleneck for in vivo experiments is the low water solubility of this chalcone. Consequently, we developed and validated a suitable formulation enabling in vivo administration. Cyclodextrins were used as water-soluble and nontoxic complexing agents, and the complex of Xanthohumol C and 2-hydroxypropyl-β-cyclodextrin was characterized using HPLC, HPLC-MS, NMR, and differential scanning calorimetry. The water solubility of Xanthohumol C increases with increasing concentrations of cyclodextrin. Using 50 mM 2-hydroxypropyl-β-cyclodextrin, solubility was increased 650-fold. Furthermore, in vitro bioactivity of Xanthohumol C in free and complexed form did not significantly differ, suggesting the release of Xanthohumol C from 2-hydroxypropyl-β-cyclodextrin. Finally, a small-scaled in vivo experiment in a rat model showed that after i. p. administration of the complex, Xanthohumol C can be detected in serum, the brain, and the cerebrospinal fluid at 1 and 6 h post-administration. Mean (± SD) Xanthohumol C serum concentrations after 1, 6, and 12 h were determined as 463.5 (± 120.9), 61.9 (± 13.4), and 9.3 (± 0.8) ng/mL upon i. v., and 294.3 (± 22.4), 45.5 (± 0.7), and 13 (± 1.0) ng/mL after i. p. application, respectively. Accordingly, the formulation of Xanthohumol C/2-hydroxypropyl-β-cyclodextrin is suitable for further in vivo experiments and further pharmaceutical research aiming for the determination of its neuroregenerative potential in animal disease models.
Activation–relaxation processes and related effects in quantum conductance of molecular junctions
Authors: Gasparyan F , Boichuk N , Vitusevich S 
Published: October 2019

Abstract
We reveal the comparative relationship between small changes in quantum conductivity behavior for molecular junctions. We clarify the mechanisms of acquiring and losing additional thermal activation energy during average current flow in a gold-1,4 benzenediamine (BDA)-gold molecular junction and explain the quantum conductance modulation process. Small changes in working temperature lead to a change in quantum conductivity, which is reflected in random telegraph signal behavior. We demonstrate the high sensitivity of the BDA molecules to small changes in temperature. For BDA molecules, conductance thermo-sensitivity values are relatively high near to

0.8
÷
1.6

×

10

−
7

Ω

−
1

K

−
1

.

This advantage can be used to measure weak variations in the ambient temperature. We show that the additional thermal energy arising from the change in temperature can impact on the strength of the electrode-molecule coupling, on the modulation of quantum conductivity. Local changes in quantum conductance of the order of quanta or smaller are conditioned by small random changes in the working regime arising from some of the activation processes. On the basis of the modulation of conductance, we calculate the magnitude of the spring constant of the 1,4 benzenediamine molecule as

k

s

≈
7.1
×

10

−
3

N

m

−
1

at the stretching length of 0.03 nm for the Au−NH2 molecular junction.
End-to-end test of an online adaptive treatment procedure in MR-guided radiotherapy using a phantom with anthropomorphic structures
Authors: Elter A , Dorsch S , Mann P , Runz A , Johnen W , Spindeldreier C K , Klüter S , Karger C P 
Published: October 2019

Abstract
Online adaptive treatment procedures in magnetic resonance (MR)-guided radiotherapy (MRgRT) allow compensating for inter-fractional anatomical variations in the patient. Clinical implementation of these procedures, however, requires specific end-to-end tests to validate the treatment chain including imaging, treatment planning, positioning, treatment plan adaption and accurate dose delivery. For this purpose, a new phantom with reproducibly adjustable anthropomorphic structures has been developed. These structures can be filled either with contrast materials providing anthropomorphic image contrast in MR and CT or with polymer dosimetry gel (PG) allowing for 3D dose measurements. To test an adaptive workflow at a 0.35 T MR-Linac, the phantom was employed in two settings simulating inter-fractional anatomical variations within the patient. The settings included two PG-filled structures representing a tumour and an adjacent organ at risk (OAR) as well as five additional structures. After generating a treatment plan, three irradiation experiments were performed: (i) delivering the treatment plan to the phantom in reference setting, (ii) delivering the treatment plan after changing the phantom to a displaced setting without adaption, and (iii) adapting the treatment plan online to the new setting and delivering it to the phantom. PG measurements revealed a homogeneous tumour coverage and OAR sparing for experiment (i) and a significant under-dosage in the PTV (down to 45% of the prescribed dose) and over-dosage in the OAR (up to 180% relative to the planned dose) in experiment (ii). In experiment (iii), a uniform dose in the PTV and a significantly reduced dose in the OAR was obtained, well-comparable to that of experiment (i) where no adaption of the treatment plan was necessary. PG measurements were well comparable with the corresponding treatment plan in all irradiation experiments. The developed phantom can be used to perform end-to-end tests of online adaptive treatment procedures at MR-Linac devices before introducing them to patients.
Anomalous caustics and Veselago focusing in 8-Pmmn borophene p–n junctions with arbitrary junction directions
Authors: Zhang Shu-Hui , Yang Wen 
Published: October 2019

Abstract
Negative refraction usually demands complex structure engineering while it is very natural for massless Dirac fermions (MDFs) across the p–n junction (PNJ), this leads to Dirac electron optics. The emergent Dirac materials may exhibit hitherto unidentified phenomenon due to their nontrivial band structures in contrast to the isotropic MDFs in graphene. Here, as a specific example, we explore the negative refraction induced caustics and Veselago focusing of tilted MDFs across 8-Pmmn borophene PNJs. To this aim, we develop a technique to effectively construct the electronic Green’s function (GF) in PNJs with arbitrary junction directions. Based on analytical discussions and numerical calculations, we demonstrate the strong dependence of interference pattern on the junction direction. As the junction direction perpendicular to the tilt direction, Veselago focusing or normal caustics (similar to that in graphene) appears resting on the doping configuration of the PNJs, otherwise anomalous caustics (different from that in graphene) occurs which is manipulated by the junction direction and the doping configuration. Finally, the developed GF technique is generally promising to uncover the unique transport of emergent MDFs, and the discovered anomalous caustics makes tilted MDFs potential applications in Dirac electron optics.
Bell inequalities tailored to the Greenberger–Horne–Zeilinger states of arbitrary local dimension
Authors: Augusiak R , Salavrakos A , Tura J , Acín A 
Published: October 2019

Abstract
In device-independent quantum information processing Bell inequalities are not only used as detectors of nonlocality, but also as certificates of relevant quantum properties. In order for these certificates to work, one very often needs Bell inequalities that are maximally violated by specific quantum states. Recently, in Salavrakos et al (2017 Phys. Rev. Lett.
119 040402) a general class of Bell inequalities, with arbitrary numbers of measurements and outcomes, has been designed, which are maximally violated by the maximally entangled states of two quantum systems of arbitrary dimension. In this work, we generalize these results to the multipartite scenario and obtain a general class of Bell inequalities maximally violated by the Greenberger–Horne–Zeilinger states of any number of parties and any local dimension. We then derive analytically their maximal quantum and nonsignaling values. We also obtain analytically the bound for detecting genuine nonlocality and compute the fully local bound for a few exemplary cases. Moreover, we consider the question of adapting this class of inequalities to partially entangled Greenberger–Horne–Zeilinger-like states for some special cases of low dimension and small number of parties. Through numerical methods, we find classes of inequalities maximally violated by these partially entangled states.
Inflammatory Markers and Incidence of Hospitalization With Infection in Chronic Kidney Disease
Authors: Ishigami Junichi , Taliercio Jonathan , I  Feldman Harold , Srivastava Anand , Townsend Raymond , L  Cohen Debbie , Horwitz Edward , Rao Panduranga , Charleston Jeanne , Fink Jeffrey C , Ricardo Ana C , Sondheimer James , Chen Teresa K , Wolf Myles , Isakova Tamara , Appel Lawrence J , Matsushita Kunihiro ,   for the CRIC Study Investigators
Published: October 2019

Abstract
Persons with chronic kidney disease (CKD) are at high risk of infection. While low-grade inflammation could impair immune response, it is unknown whether inflammatory markers are associated with infection risk in this clinical population. Using 2003–2013 data from the Chronic Renal Insufficiency Cohort Study (3,597 participants with CKD), we assessed the association of baseline plasma levels of 4 inflammatory markers (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 receptor antagonist (IL-1RA), and transforming growth factor-β (TGF-β)) with incident hospitalization with major infection (pneumonia, urinary tract infection, cellulitis and osteomyelitis, and bacteremia and sepsis). During follow-up (median 7.5 years), 36% (n = 1,290) had incident hospitalization with major infection. In multivariable Cox analyses with each inflammatory marker modeled as a restricted cubic spline, higher levels of IL-6 and TNF-α were monotonically associated with increased risk of hospitalization with major infection (for 95th vs. 5th percentile, hazard ratio = 2.11 (95% confidence interval: 1.68, 2.66) for IL-6 and 1.88 (95% confidence interval: 1.51, 2.33) for TNF-α), while corresponding associations for IL-1RA or TGF-β were nonsignificant. Thus, higher plasma levels of IL-6 and TNF-α, but not IL-1RA or TGF-β, were significantly associated with increased risk of hospitalization with major infection. Future studies should investigate whether inflammatory pathways that involve IL-6 and TNF-α increase susceptibility to infection among individuals with CKD.
Implementing Evidence-Based Practice in a Dutch Social Work Organisation: A Shared Responsibility
Authors: van der Zwet Renske J M , Beneken genaamd Kolmer Deirdre M , Schalk René , Van Regenmortel Tine 
Published: October 2019

Abstract
This article presents the findings from a case study, exploring the factors that support and impede implementation of evidence-based practice (EBP) in a Dutch social work organisation that has recently committed to EBP. Qualitative data were gathered from semi-structured interviews with ten staff members and twelve social workers (service providers for adults and families). The organisational model for EBP implementation, recently developed by Plath, was used to examine how EBP was implemented and the factors that support and impede it. Findings revealed that EBP occurs predominantly at the organisational level. Research & Development (R&D) staff take responsibility for the key steps of gathering, appraising and translating research insights into practice activities, whilst social workers are primarily involved in implementing interventions. R&D is also involved in the internal evaluation of interventions in order to support ongoing practice development. Several factors affecting EBP implementation and facilitative strategies have been identified. Most of these are congruent with the organisational model for EBP implementation, with the exception of two impacting factors (negative attitudes about EBP and an organisational culture that values and encourages innovation and learning) and one facilitative strategy (research partnerships). These findings were used to develop the model further.
Genetic diversity and reproductive biology of the dioecious and epiphytic bromeliad Aechmea mariae-reginae (Bromeliaceae) in Costa Rica: implications for its conservation
Authors: Cascante-Marín Alfredo , Trejos Christian , Madrigal Ruth , Fuchs Eric J 
Published: October 2019

AbstractEcological traits and pollination mode associated with dioecious sexual expression in plants are likely to influence their reproductive success and levels of genetic diversity. Dioecy is an uncommon condition in Bromeliaceae. Currently, there is limited information on the reproductive ecology and genetics of dioecious and epiphytic bromeliads. Therefore, we studied the reproductive biology and genetic diversity of the epiphytic and dioecious bromeliad Aechmea mariae-reginae in Costa Rica. Flowering of pistillate and staminate plants in one population showed high synchrony and were pollinated by non-hermit hummingbirds. Sex ratio was biased to males (3.5:1). Fruit set was relatively high (68%) but there was high female reproductive variance (C. V. = 59.7%). The species is capable of parthenocarpic fruit production. Using eight nuclear microsatellite markers and six populations, we found moderate to high levels of genetic variation (HE = 0.571–0.726). Populations showed significant genetic structure (G'ST = 0.385) and Bayesian population assignment grouped them into lowland and montane clusters. Isolated montane populations had slightly lower genetic diversity probably due to lower effective population size caused by biased sex ratios and recent habitat fragmentation that limits long-distance pollinator movements and results in isolation by distance. If habitat fragmentation and isolation persist, populations in montane habitats may be at higher risk of decline and extinction.