Joint Moments and Powers in Healthy Young Adults During Stair Negotiation

The primary objective of this study was to determine lower limb joint moments and powers of stair negotiation in healthy young individuals. These results will provide baseline information for future studies with elderly and clinical populations designed to prevent falls that occur during stair negotiation. In previous stair negotiation studies, researchers investigated joint moments and powers initiating stair ascent in front of the stairway. Starting farther away from the stairway allows individuals to stabilize gait velocity and thus, exclude the influence of velocity on joint moments and powers generated during stair ascent. Ten young, healthy individuals underwent gait analysis during stair negotiation. Two way repeated measures ANOVA was used to determine the differences between two different conditions, starting farther away from the stairway (C1) and starting in front of the stairway (C2), for two consecutive steps (s1 and s2) on the stairway performed by the same leg. A motion analysis system was used to collect the three-dimensional spatial trajectories of the markers (joint angle data). Ground reaction forces were collected using two AMTI force platforms embedded in the first and the third stair treads. Our results demonstrated that ankle power absorption (PA1) was significantly higher during the s1 and s2 in C1 than during the s1 in C2. PA1 was significantly greater during s2 than during s1 in condition 2. Ankle power generation (PA2) was significantly higher during s2 than s1 in C1. The hip power absorption (PH2) was significantly higher during s1 in C1 than during s2 in C1, and s1 and s2 in C2. PH2 was significantly higher during s1 in C2 than s2 in both C1 and C2. These findings iv showed that the way individuals approach stairs will have a different affect on the ankle and the hip joints which has to be considered in future studies in stair negotiation

Eros, Agape and Ethnos: Proposal for a Critical Analysis of the Public Discourse on Religion, Homosexuality and Nationalism in the Context of the Western Balkans

U ovom radu ce se istraživati da li se i kako dihotomija izmedu religije i (homo)seksualnosti odnosi na religijsko-politicke konfiguracije i grupisanja u razlicitim nacionalnim kontekstima Zapadnog Balkana. Analiza odnosa izmedu etnonacionalizma, religije i (posebno) homoseksualnosti u postkonfliktnim društvima objašnjava kako funkcioniše religijski nacionalizam, privilegujuci heteronormativnost, provocirajuci i podržavajuci homofobnu kulturu. U radu autori predlažu okvir za analizu javnog diskursa koji ce doprineti savremenoj naucnoj debate o strategijama i ideološkim pretpostavkama, interesima i posledicama trenutne konstrukcije (homo)seksualnosti i religije u javnom diskursu. Ovo komparativno istraživanje fokusira se na tri razlicita medijska i religijskokulturološka konteksta: Srbiju, Bosnu i Hercegovinu i Hrvatsku

Do lower-extremity joint dynamics change when stair negotiation is initiated with a self-selected comfortable gait speed?

Previous research on the biomechanics of stair negotiation has ignored the effect of the approaching speed. We examined if initiating stair ascent with a comfortable self-selected speed can affect the lower-extremity joint moments and powers as compared to initiating stair ascent directly in front of the stairs. Healthy young adults ascended a custom-built staircase instrumented with force platforms. Kinematics and kinetics data were collected simultaneously for two conditions: starting from farther away and starting in front of the stairs and analyzed at the first and second ipsilateral steps. Results showed that for the first step, participants produced greater peak knee extensor moment, peak hip extensor and flexor moments and peak hip positive power while starting from farther away. Also, for both the conditions combined, participants generated lesser peak ankle plantiflexor, greater peak knee flexor moment, lesser peak ankle negative power and greater peak hip negative power while encountering the first step. These results identify the importance of the starting position in experiments dealing with biomechanics of stair negotiation. Further, these findings have important implications for studying stair ascent characteristics of other populations such as older adults

Molar-mass distribution of urea-formaldehyde resins of different degrees of polymerisation by MALDI-TOF mass spectrometry

This paper describes some results obtained in an investigation of urea-formaldehyde (UF) resins of different degrees of polymerisation by matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry (MS). MALDI-TOF MS proved to be an appropriate technique for analyzing these types of polymers, bearing in mind that the results of the analysis correspond with previous physical and chemical measurements. This technique enables a relatively swift determination of the degree of polymerrisation through the monitoring of key changes in the structure of a polymer. Thus, in the analysis of UF resins, it may be possible to monitor a decrease in the intensity of the monohydroxymethyl urea (MMU) signal, which corresponds to an increase of the mass spectra values in the mass range of higher homologues, above 1000 g mol(-1). A noticeable difference concerns the signal intensities in the higher mass ranges (up to 1400 g mol(-1)), which corresponds to more branched and longer homologues of the polymers. Especially, a significantly more intensive signal of MMU was registered. The average molecular weight (MW) of the examined samples was between 936 and 1324 g mol(-1), with a maximal deviation of 20 %, depending on the ratios of the reactants

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer

Ca2+/Calmodulin-Dependent Protein Kinase Kinase Is Not Involved in Hypothalamic AMP-Activated Protein Kinase Activation by Neuroglucopenia

Hypoglycemia and neuroglucopenia stimulate AMP-activated protein kinase (AMPK) activity in the hypothalamus and this plays an important role in the counterregulatory responses, i.e. increased food intake and secretion of glucagon, corticosterone and catecholamines. Several upstream kinases that activate AMPK have been identified including Ca2+/Calmodulin-dependent protein kinase kinase (CaMKK), which is highly expressed in neurons. However, the involvement of CaMKK in neuroglucopenia-induced activation of AMPK in the hypothalamus has not been tested. To determine whether neuroglucopenia-induced AMPK activation is mediated by CaMKK, we tested whether STO-609 (STO), a CaMKK inhibitor, would block the effects of 2-deoxy-D-glucose (2DG)-induced neuroglucopenia both ex vivo on brain sections and in vivo. Preincubation of rat brain sections with STO blocked KCl-induced α1 and α2-AMPK activation but did not affect AMPK activation by 2DG in the medio-basal hypothalamus. To confirm these findings in vivo, STO was pre-administrated intracerebroventricularly (ICV) in rats 30 min before 2DG ICV injection (40 µmol) to induce neuroglucopenia. 2DG-induced neuroglucopenia lead to a significant increase in glycemia and food intake compared to saline-injected control rats. ICV pre-administration of STO (5, 20 or 50 nmol) did not affect 2DG-induced hyperglycemia and food intake. Importantly, activation of hypothalamic α1 and α2-AMPK by 2DG was not affected by ICV pre-administration of STO. In conclusion, activation of hypothalamic AMPK by 2DG-induced neuroglucopenia is not mediated by CaMKK

Defining the genetic control of human blood plasma N-glycome using genome-wide association study

Glycosylation is a common post-translational modification of proteins. Glycosylation is associated with a number of human diseases. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people measured by Ultra Performance Liquid Chromatography (UPLC) technology. Starting with the 36 original traits measured by UPLC, we computed an additional 77 derived traits leading to a total of 113 glycan traits. We studied associations between these traits and genetic polymorphisms located on human autosomes. We discovered and replicated 12 loci. This allowed us to demonstrate an overlap in genetic control between total plasma protein and IgG glycosylation. The majority of revealed loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3 and MGAT5) and a known regulator of plasma protein fucosylation (HNF1A). However, we also found loci that could possibly reflect other more complex aspects of glycosylation process. Functional genomic annotation suggested the role of several genes including DERL3, CHCHD10, TMEM121, IGH and IKZF1. The hypotheses we generated may serve as a starting point for further functional studies in this research area

Post-translational regulation contributes to the loss of LKB1 expression through SIRT1 deacetylase in osteosarcomas

background: The most prevalent form of bone cancer is osteosarcoma (OS), which is associated with poor prognosis in case of metastases formation. Mice harbouring liver kinase B1 (LKB1+/−) develop osteoblastoma-like tumours. Therefore, we asked whether loss of LKB1 gene has a role in the pathogenesis of human OS. methods: Osteosarcomas (n=259) were screened for LKB1 and sirtuin 1 (SIRT1) protein expression using immunohistochemistry and western blot. Those cases were also screened for LKB1 genetic alterations by next-generation sequencing, Sanger sequencing, restriction fragment length polymorphism and fluorescence in situ hybridisation approaches. We studied LKB1 protein degradation through SIRT1 expression. MicroRNA expression investigations were also conducted to identify the microRNAs involved in the SIRT1/LKB1 pathway. results: Forty-one per cent (106 out of 259) OS had lost LKB1 protein expression with no evident genetic anomalies. We obtained evidence that SIRT1 impairs LKB1 protein stability, and that SIRT1 depletion leads to accumulation of LKB1 in OS cell lines resulting in growth arrest. Further investigations revealed the role of miR-204 in the regulation of SIRT1 expression, which impairs LKB1 stability. conclusions: We demonstrated the involvement of sequential regulation of miR-204/SIRT1/LKB1 in OS cases and showed a mechanism for the loss of expression of LKB1 tumour suppressor in this malignancy

DNA Repair in Human Pluripotent Stem Cells Is Distinct from That in Non-Pluripotent Human Cells

The potential for human disease treatment using human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells (iPSCs), also carries the risk of added genomic instability. Genomic instability is most often linked to DNA repair deficiencies, which indicates that screening/characterization of possible repair deficiencies in pluripotent human stem cells should be a necessary step prior to their clinical and research use. In this study, a comparison of DNA repair pathways in pluripotent cells, as compared to those in non-pluripotent cells, demonstrated that DNA repair capacities of pluripotent cell lines were more heterogeneous than those of differentiated lines examined and were generally greater. Although pluripotent cells had high DNA repair capacities for nucleotide excision repair, we show that ultraviolet radiation at low fluxes induced an apoptotic response in these cells, while differentiated cells lacked response to this stimulus, and note that pluripotent cells had a similar apoptotic response to alkylating agent damage. This sensitivity of pluripotent cells to damage is notable since viable pluripotent cells exhibit less ultraviolet light-induced DNA damage than do differentiated cells that receive the same flux. In addition, the importance of screening pluripotent cells for DNA repair defects was highlighted by an iPSC line that demonstrated a normal spectral karyotype, but showed both microsatellite instability and reduced DNA repair capacities in three out of four DNA repair pathways examined. Together, these results demonstrate a need to evaluate DNA repair capacities in pluripotent cell lines, in order to characterize their genomic stability, prior to their pre-clinical and clinical use