Polymeric materials are promising for solar cell applications. High‐molecular‐weight and soluble polyN‐9'‐heptadecanyl‐2,7‐carbazole‐alt‐5,5‐(4',7'‐di‐ 2‐thienyl‐2',1',3'‐benzothiadiazole) is ...synthesized by either a Stille or Suzuki coupling reaction. Electrochemical and optical characterization of this thermally and air‐stable polymeric material is reported, and bulk heretojunction polymer/fullerene photovoltaic devices are fabricated.
The outcome of patients with resistant phenotypes of acute lymphoblastic leukemia (ALL) or those who relapse remains poor. We investigated the mechanism of cell death induced by metformin in Bp- and ...T-ALL cell models and primary cells, and show that metformin effectively induces apoptosis in ALL cells. Metformin activated AMPK, down-regulated the unfolded protein response (UPR) demonstrated by significant decrease in the main UPR regulator GRP78, and led to UPR-mediated cell death via up-regulation of the ER stress/UPR cell death mediators IRE1α and CHOP. Using shRNA, we demonstrate that metformin-induced apoptosis is AMPK-dependent since AMPK knock-down rescued ALL cells, which correlated with down-regulation of IRE1α and CHOP and restoration of the UPR/GRP78 function. Additionally rapamycin, a known inhibitor of mTOR-dependent protein synthesis, rescued cells from metformin-induced apoptosis and down-regulated CHOP expression. Finally, metformin induced PIM-2 kinase activity and co-treatment of ALL cells with a PIM-1/2 kinase inhibitor plus metformin synergistically increased cell death, suggesting a buffering role for PIM-2 in metformin's cytotoxicity. Similar synergism was seen with agents targeting Akt in combination with metformin, supporting our original postulate that AMPK and Akt exert opposite regulatory roles on UPR activity in ALL. Taken together, our data indicate that metformin induces ALL cell death by triggering ER and proteotoxic stress and simultaneously down-regulating the physiologic UPR response responsible for effectively buffering proteotoxic stress. Our findings provide evidence for a role of metformin in ALL therapy and support strategies targeting synthetic lethal interactions with Akt and PIM kinases as suitable for future consideration for clinical translation in ALL.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Purpose Transgender youth represent a vulnerable population at risk for negative mental health outcomes including depression, anxiety, self-harm, and suicidality. Limited data exist to ...compare the mental health of transgender adolescents and emerging adults to cisgender youth accessing community-based clinical services; the present study aimed to fill this gap. Methods A retrospective cohort study of electronic health record data from 180 transgender patients aged 12–29 years seen between 2002 and 2011 at a Boston-based community health center was performed. The 106 female-to-male (FTM) and 74 male-to-female (MTF) patients were matched on gender identity, age, visit date, and race/ethnicity to cisgender controls. Mental health outcomes were extracted and analyzed using conditional logistic regression models. Logistic regression models compared FTM with MTF youth on mental health outcomes. Results The sample (N = 360) had a mean age of 19.6 years (standard deviation, 3.0); 43% white, 33% racial/ethnic minority, and 24% race/ethnicity unknown. Compared with cisgender matched controls, transgender youth had a twofold to threefold increased risk of depression, anxiety disorder, suicidal ideation, suicide attempt, self-harm without lethal intent, and both inpatient and outpatient mental health treatment (all p < .05). No statistically significant differences in mental health outcomes were observed comparing FTM and MTF patients, adjusting for age, race/ethnicity, and hormone use. Conclusions Transgender youth were found to have a disparity in negative mental health outcomes compared with cisgender youth, with equally high burden in FTM and MTF patients. Identifying gender identity differences in clinical settings and providing appropriate services and supports are important steps in addressing this disparity.
Cell-penetrating peptides (CPPs) have been used in basic and preclinical research in the past 30 years to facilitate drug delivery into target cells. However, translation toward the clinic has not ...been successful so far. Here, we studied the pharmacokinetic (PK) and biodistribution profiles of Shuttle cell-penetrating peptides (S-CPP) in rodents, combined or not with an immunoglobulin G (IgG) cargo. We compared two enantiomers of S-CPP that contain both a protein transduction domain and an endosomal escape domain, with previously shown capacity for cytoplasmic delivery. The plasma concentration versus time curve of both radiolabelled S-CPPs required a two-compartment PK analytical model, which showed a fast distribution phase (t
α ranging from 1.25 to 3 min) followed by a slower elimination phase (t
β ranging from 5 to 15 h) after intravenous injection. Cargo IgG combined to S-CPPs displayed longer elimination half-life, of up to 25 h. The fast decrease in plasma concentration of S-CPPs was associated with an accumulation in target organs assessed at 1 and 5 h post-injection, particularly in the liver. In addition, in situ cerebral perfusion (ISCP) of L-S-CPP yielded a brain uptake coefficient of 7.2 ± 1.1 µl g
s
, consistent with penetration across the blood-brain barrier (BBB), without damaging its integrity in vivo. No sign of peripheral toxicity was detected either by examining hematologic and biochemical blood parameters, or by measuring cytokine levels in plasma. In conclusion, S-CPPs are promising non-toxic transport vectors for improved tissue distribution of drug cargos in vivo.
L’os participe au métabolisme phosphocalcique mais aussi énergétique. Il sécrète l’ostéocalcine d’origine ostéoblastique, hormone insulino-sécrétante/-sensibilisante qui diminuerait la masse grasse ...(MG), et le FGF-23 d’origine ostéoclastique, phosphaturiant et marqueur d’insulino-résistance. Les relations entre insulinorésistance, leptine, MG et os sont contradictoires. L’objectif de cette étude était d’évaluer l’ostéocalcine et le FGF23 dans des pathologies différant par la MG et l’insulinorésistance et notamment dans les lipodystrophies, un modèle d’insulino-résistance extrême sans obésité avec hypoleptinémie. La population, issue du PHRC-Clin.gov2009-AO-1169-48, a été divisée en 5 groupes : lipodystrophies LMNA-mutées (LDM, n = 11), lipodystrophies non mutées (LDNM, n = 21), obèses diabétiques (OB, n = 13), obèses non diabétiques (OND, n = 13), témoins normo-pondéraux (T, n = 19). Les paramètres phospho-calciques, métaboliques et de composition corporelle (DEXA) ont été comparés entre ces 5 groupes. Ostéocalcine, crosslaps, leptine, IMC, MG, masse maigre/taille2 , glycémie-C-peptide à jeun, HbA1c , HOMA-IR différaient entre ces 5 groupes avec une tendance pour T score, calcémie et 25OHvitD. Phosphorémie, calciurie, PTH, FGF23 étaient similaires. La comparaison des groupes 2 à 2 retrouvait une ostéocalcinémie inférieure chez les LDM médiane (IQR) :12 (10–14) ng/mL comparés aux OND (17 (13–21), et chez les LDM et LDNM (14 (12–18)) comparés aux témoins (24 (22–29)), et d’autant plus basse que l’HOMA-IR était plus élevé (LDM : 4 (0.6–12) ; LDNM : 3 (2–5) ; OD : 4(3–6) ; OND : 1.6 (1–3) ; T : 1.1 (0.8–1.4)) sans relation avec la MG (LDM : 23 (18–29) ; LDNM : 15 (12–18) ; OD : 41 (37–43) ; OND 50 (48–62) ; T : 17 (12–22)) kg ou la leptine (LDM : 15(8–22) ; LDNM : 6 (4–13) ; OD : 27 (24–41) ; OND : 49 (32–67) ; T : 5 (4–12) ng/mL. Conclusion L’ostéocalcine est d’autant plus basse que l’insulinorésistance est élevée quelle que soit la masse grasse et la leptine, sans différence significative du FGF23 et du T score. Cette diminution marquerait un dysfonctionnement ostéoblastique primitif ou secondaire.
Background:
Recent studies suggest that gastrointestinal (GI) microbes play a part in the pathogenesis of Crohn's disease (CD).
Methods:
Fecal samples were collected from 16 healthy individuals and ...16 CD patients (age‐ and sex‐matched). The DNA extracted from these samples were subjected to two different methods of microbiome analysis. Specific bacterial groups were quantified by real‐time polymerase chain reaction (PCR) methods using primers designed using a high‐throughput in‐house bioinformatics pipeline. The same DNA extracts were also used to produce fluorescently labeled cRNA amplicons to interrogate a custom‐designed phylogenetic microarray for intestinal bacteria.
Results:
Even though the intersubject variability was high, differences in the fecal microbiomes of healthy and CD patients were detected. Faecalibacterium prausnitzii and Escherichia coli were more represented in healthy and ileal CD patients, respectively. Additionally, probes specific for Ruminococcus bromii, Oscillibacter valericigenes, Bifidobacterium bifidum, and Eubacterium rectale produced stronger hybridization signals with the DNA samples from healthy subjects. Conversely, species overrepresented in CD patients were E. coli, Enterococcus faecium, and species from the Proteobacteria not normally found in the healthy human GI tract. Furthermore, we detected “healthy specific” molecular species or operational taxonomic units (OTUs) that are not closely related to any known species (Faecalibacterium, Subdoligranulum, and Oscillospora species), indicating that the phylogenetic dysbiosis is broader than at strain or species level.
Conclusions:
These two techniques of microbiome analysis provided a statistically robust new picture of the dysbiosis in fecal microbiota from ileal CD patients. Specifically, we identified a set of six species discriminant for CD, which provides a preliminary diagnostic tool. (Inflamm Bowel Dis 2011;)
Gravitational gauge theories with de Sitter, Poincaré and affine symmetry group are investigated under the aspect of the breakdown of the initial symmetry group down to the Lorentz subgroup. As ...opposed to the nonlinear realization approach, in the dynamical symmetry breaking procedure, the structure subgroup is not chosen arbitrarily, but is dictated by the symmetry of the groundstate of a Higgs field. We review the theory of spontaneously broken de Sitter gravity by Stelle and West and apply a similar approach to the case of the Poincaré and affine groups. We will find that the Poincaré case is almost trivial. The translational Higgs field reveals itself as pure gauge, i.e., it is expressed entirely in terms of the Nambu–Goldstone bosons and does not appear in the Lagrangian after the symmetry breaking. The same holds for the translational part of the affine group. The Higgs field provoking the breakdown of the general linear group leads to the determination of the Lorentzian signature of the metric in the groundstate. We show that the Higgs field remains in its groundstate, i.e., that the metric will have Lorentzian signature, unless we introduce matter fields that explicitely couple to the symmetric part of the connection. Furthermore, we present arguments that the Lorentzian signature is actually the only possible choice for physical spacetime, since the symmetry breaking mechanism works only if the stability subgroup is taken to be the Lorentz group. The other four-dimensional rotation groups are therefore ruled out not only on physical, but also on theoretical grounds. Finally, we show that some features, like the necessity of the introduction of a dilaton field, that seem artificial in the context of the affine theory, appear most natural if the gauge group is taken to be the special linear group in five dimensions. We also present an alternative model which is based on the spinor representation of the Lorentz group and is especially adopted to the description of spinor fields in a general linear covariant way, without the use of the infinite dimensional representations which are usually considered to be unavoidable.
Conjugated polymers that can detect and transduce chemical or physical information into an optical or electrical signal form the basis of this review. Aspects such as thermo‐ and biochromism, polymer ...conformation, and electrostatic effects are covered. Uses of these smart materials, for example, as ion‐responsive fluorescent solid‐state sensors (see Figure), are also discussed.
Human shields mediate sexual conflict in a top predator Steyaert, S. M. J. G.; Leclerc, M.; Pelletier, F. ...
Proceedings - Royal Society. Biological sciences/Proceedings - Royal Society. Biological Sciences,
06/2016, Letnik:
283, Številka:
1833
Journal Article
Recenzirano
Odprti dostop
Selecting the right habitat in a risky landscape is crucial for an individual's survival and reproduction. In predator–prey systems, prey often can anticipate the habitat use of their main predator ...and may use protective associates (i.e. typically an apex predator) as shields against predation. Although never tested, such mechanisms should also evolve in systems in which sexual conflict affects offspring survival. Here, we assessed the relationship between offspring survival and habitat selection, as well as the use of protective associates, in a system in which sexually selected infanticide (SSI), rather than interspecific predation, affects offspring survival. We used the Scandinavian brown bear (Ursus arctos) population with SSI in a human-dominated landscape as our model system. Bears, especially adult males, generally avoid humans in our study system. We used resource selection functions to contrast habitat selection of GPS-collared mothers that were successful (i.e. surviving litters, n = 19) and unsuccessful (i.e. complete litter loss, n = 11) in keeping their young during the mating season (2005–2012). Habitat selection was indeed a predictor of litter survival. Successful mothers were more likely to use humans as protective associates, whereas unsuccessful mothers avoided humans. Our results suggest that principles of predator–prey and fear ecology theory (e.g. non-consumptive and cascading effects) can also be applied to the context of sexual conflict.
•A new theory for the interpretation of size-dependency of the fracture energy of concrete.•The theory is a simple and mechanical interpretation for the boundary effect theory.•A new experimental ...protocol based on wedge splitting test and digital image correlation.•The new protocol is simpler than the existing SBEM protocol.•Validations were performed experimentally on two different concrete mixtures.
The fracture energy constitutes an important input parameter for non-linear finite element analysis of concrete structures. Characterization of such parameter based on standard RILEM three-point bending test or wedge splitting test is known to depend on the size of the specimen. For the assessment example of large hydraulic structures using non-linear finite elements, it is important to develop an experimental protocol for characterizing a size-independent fracture energy, or asymptotic fracture energy representative of the size of these structures.
Characterization of the asymptotic fracture energy requires specimens with very large sizes and thus represents an important experimental challenge. This work aims to develop a new experimental protocol based on wedge splitting test on specimen with moderate size and using digital image correlation technique.
The new protocol is based on the disturbed fracture process zone (DFPZ) theory developed in this work, as an interpretation theory for the boundary effect theory of Duan et al. 8. It uses the same hypothesis of bilinear distribution of the local fracture energy as in the simplified boundary effect method (SBEM) (Abdalla and Karihaloo 1, Karihaloo et al. 21) but requires only one set of specimens with a specific notch over depth (a/D) ratio rather than two sets of specimens with two different a/D ratios.
In order to validate the developed approach and theory, an experimental programme of 14 concrete specimens is conducted. Two concrete mixtures are considered with two maximum aggregate sizes: 38 mm and 76 mm, representative of hydraulic structures.
Assessment of the fracture energy using the new protocol and the protocol based on SBEM resulted in similar values for both mixtures and thus validates the new developed theory.
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