Depressive symptoms, frailty, and adverse outcomes among kidney transplant recipients

Depressive symptoms and frailty are each independently associated with morbidity and mortality in kidney transplant (KT) recipients. We hypothesized that having both depressive symptoms and frailty would be synergistic and worse than the independent effect of each. In a multicenter cohort study of 773 KT recipients, we measured the Fried frailty phenotype and the modified 18â question Center for Epidemiologic Studiesâ Depression Scale (CESâ D). Using adjusted Poisson regression and survival analysis, we tested whether depressive symptoms (CESâ D score > 14) and frailty were associated with KT length of stay (LOS), deathâ censored graft failure (DCGF), and mortality. At KT admission, 10.0% of patients exhibited depressive symptoms, 16.3% were frail, and 3.6% had both. Recipients with depressive symptoms were more likely to be frail (aOR = 3.97, 95% CI: 2.28â 6.91, P < 0.001). Recipients with both depressive symptoms and frailty had a 1.88 times (95% CI: 1.70â 2.08, P < 0.001) longer LOS, 6.20â fold (95% CI:1.67â 22.95, P < 0.01) increased risk of DCGF, and 2.62â fold (95% CI:1.03â 6.70, P = 0.04) increased risk of mortality, compared to those who were nonfrail and without depressive symptoms. There was only evidence of synergistic effect of frailty and depressive symptoms on length of stay (P for interaction < 0.001). Interventions aimed at reducing preâ KT depressive symptoms and frailty should be explored for their impact on postâ KT outcomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146305/1/ctr13391_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146305/2/ctr13391.pd

Notch Promotes Neural Lineage Entry by Pluripotent Embryonic Stem Cells

A central challenge in embryonic stem (ES) cell biology is to understand how to impose direction on primary lineage commitment. In basal culture conditions, the majority of ES cells convert asynchronously into neural cells. However, many cells resist differentiation and others adopt nonneural fates. Mosaic activation of the neural reporter Sox-green fluorescent protein suggests regulation by cell-cell interactions. We detected expression of Notch receptors and ligands in mouse ES cells and investigated the role of this pathway. Genetic manipulation to activate Notch constitutively does not alter the stem cell phenotype. However, upon withdrawal of self-renewal stimuli, differentiation is directed rapidly and exclusively into the neural lineage. Conversely, pharmacological or genetic interference with Notch signalling suppresses the neural fate choice. Notch promotion of neural commitment requires parallel signalling through the fibroblast growth factor receptor. Stromal cells expressing Notch ligand stimulate neural specification of human ES cells, indicating that this is a conserved pathway in pluripotent stem cells. These findings define an unexpected and decisive role for Notch in ES cell fate determination. Limiting activation of endogenous Notch results in heterogeneous lineage commitment. Manipulation of Notch signalling is therefore likely to be a key factor in taking command of ES cell lineage choice

PhD courses and the intersectoral experience:a comprehensive survey

Abstract It has been found that most PhD graduates (>85%) do not achieve a long-term academic career and thus there is a growing need to re-imagine PhD education that incentivizes doctoral students to engage with research consumers, not only within their discipline, but also, across other disciplines and sectors to have real social impact for an improved society. The aim of this work is to identify intersectoral/interdisciplinary courses that are considered to broaden student career outside and inside academia. For this purpose, a survey was designed to identify modules which lead to the improvement of students’ skills while an analysis of their attributes was also performed. Two target groups have been considered: (a) young researchers and (b) program directors each of which can provide different information regarding the courses of interest. 52 students and 11 directors from 5 European Universities, participated in the study. An absence of such courses in the standard PhD program was observed, while any intersectoral/interdisciplinary activities were conducted outside the PhD program, and organized by collaboration of academia and other organizations. The survey findings reveal the need to restructure the PhD programs

Monometallic and Bimetallic Titanium κ¹‑Amidinate Complexes as Olefin Polymerization Catalysts

A series of cyclopentadienyl-κ¹-amidinate titanium complexes Cp*Ti­{NC­(Ar^R)­N^<i>i</i>Pr₂}­Me₂ (Ar^R = 4-C₆H₄R, where R = H (<b>1</b>-<b>Me</b>), CF₃ (<b>5-Me</b>), ^<i>t</i>Bu (<b>6-Me</b>), or NMe₂ (<b>7-Me</b>)) with different para-substituents in the amidinate ligand were synthesized and structurally characterized, along with three bimetallic analogues: 1,4-C₆H₄{C­(N^<i>i</i>Pr₂)­N}₂{Cp*TiMe₂}₂ (<b>2-Me</b>), 1,3-C₆H₄{C­(N^<i>i</i>Pr₂)­N}₂{Cp*TiMe₂}₂ (<b>3-Me</b>), and CH₂{1,4-C₆H₄-C­(N^<i>i</i>Pr₂)­N}₂{Cp*TiMe₂}₂ (<b>4-Me</b>). ¹³C NMR spectroscopy, density function theory, and the quantum theory of atoms-in-molecules were used to evaluate the donor ability of the various NC­(Ar ^R)­N^<i>i</i>Pr₂ ligands and the influence of the Ar^R group para-substituents. Reactions of <b>1</b>-<b>Me</b> and certain homologues, as well as <b>2-Me</b>, with borate and borane reagents [CPh₃]­[BAr^F₄] (Ar^F = C₆F₅), BAr^F₃, in the absence or presence of Lewis bases or polar unsaturated substrates were carried out, forming adducts and migratory insertion products such as [Cp*Ti­{NC­(Ph)­N^<i>i</i>Pr₂}­Me­(THF)]­[BAr^F₄], [Cp*Ti­{NC­(Ph)­N^<i>i</i>Pr₂}­{MeC­(N^<i>i</i>Pr)₂}]­[BAr^F₄], and [1,4-C₆H₄{C­(N^<i>i</i>Pr₂)­N}₂{Cp*Ti­{MeC­(N^<i>i</i>Pr)₂}₂][BAr^F₄]₂. Detailed olefin copolymerization studies for forming EPDM from ethylene, propylene, and certain dienes were carried out with mono- and bimetallic catalysts and borate and borane activators. Catalyst–activator effects on polymerization productivity and polymer composition relationships were mapped. Bimetallic catalysts <b>2</b> and <b>3</b> showed cooperative effects based on electronic factors, leading to enhanced propene incorporation, but unfavorable steric effects gave lower diene content. Related but less significant electronic effects on propene affinity were found for the monometallic catalysts Cp*Ti­{NC­(Ar^R)­N^<i>i</i>Pr₂}­Me₂ as the Ar^R moiety para-substituents were varied

Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) blocks differentiation and maintains the expression of pluripotency markers in human embryonic stem cells

Human embryonic stem cells (hESCs) have enormous potential for use in pharmaceutical development and therapeutics, however to realise this potential there is a requirement for simple and reproducible cell culture methods that provide adequate numbers of cells of suitable quality. We have discovered a novel way of blocking the spontaneous differentiation of hESCs in the absence of exogenous cytokines by supplementing feeder-free conditions with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an established inhibitor of adenosine deaminase (ADA) and cyclic nucleotide phosphodiesterase- 2 (PDE2). hESCs maintained in feeder-free conditions with EHNA for more than 10 passages showed no reduction in hESC associated markers including NANOG, POU5F1 and SSEA 4 compared to cells maintained in feeder-free conditions containing basic fibroblast growth factor (bFGF). Spontaneous differentiation was reversibly suppressed by the addition of EHNA, but upon removing EHNA hESC populations underwent efficient spontaneous, multi-lineage and directed differentiation. EHNA also acts as a strong blocker of directed neuronal differentiation. Chemically distinct inhibitors of ADA and PDE2 lacked the capacity of EHNA to suppress hESC differentiation, suggesting that the effect is not driven by inhibition of either ADA or PDE2. Preliminary structure activity relationship analysis found the differentiation blocking properties of EHNA to reside in a pharmacophore comprised of a close adenine mimetic with an extended hydrophobic substituent in the 8- or 9-position. We conclude that EHNA and simple 9-alkyladenines can block directed neuronal and spontaneous differentiation in the absence of exogenous cytokine addition, and may provide a useful replacement for bFGF in large scale or cGMP compliant processes