At the University of Maryland School of Medicine, faculty and students are invited to participate in a programme dealing with the psychosocial aspects of medicine and interpersonal skills development ...(Human Dimensions in Medical Education-HDME). Utilizing a small-group format, this programme encourages discussion of attitudes and feelings on a wide range of topics in an open, supportive environment. Shortly after the programme became fully operational, first-, second- and third-year medical students evaluated their relationships with their faculty advisers using a 25-item questionnaire. Students assigned to advisers who participated in the HDME programme reported higher activity in ten behavioural areas than students of non-HDME advisers, generally reflecting closer personal relationships and greater adviser initiative in establishing relationships. In addition, HDME students felt more at ease approaching their advisers with a personal problem than did students who had not participated in the HDME programme. Programme-related activities were the most frequent source of close relationships between faculty and student programme participants. Overall results emphasized the value of faculty initiative in establishing relationships with students and the impact of opportunities for small-group interaction, whether in academic or social settings, for the development and maintenance of an institutional support system. Such opportunities for personal contact can assist students to deal more easily with the pressures of the educational process, and with conflicts among personal and professional priorities that will characterize their lives as physicians.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Reports of C-H insertions forming six-membered rings containing heteroatoms are rare due to Stevens rearrangements occurring after nucleophilic attack on the carbene by a heteroatom. Using ...donor/donor carbenes and Rh
2
(
R
-PTAD)
4
as a catalyst, we have synthesized a collection of isochroman substrates in good yield, with excellent diastereo- and enantioselectivity, and no rearrangement products were observed. Furthermore, we report the first synthesis of six-membered rings containing nitrogen by C-H insertion to form tetrahydroisoquinolines. In one case, a Stevens rearrangement product was isolated at elevated temperature from a carbamate-protected amine substrate and computational evidence suggests formation through a free ylide not bound to rhodium.
Six-membered ring oxygen and nitrogen heterocycles are formed stereoselectively by C-H insertion of donor/donor carbenes.
T cell activation, a key early event in the adaptive immune response, is subject to elaborate transcriptional control. In the present study, we examined how the activities of eight major ...transcription factor (TF) families are integrated to shape the epigenome of naive and activated CD4 and CD8 T cells. By leveraging extensive polymorphisms in evolutionarily divergent mice, we identified the 'heavy lifters' positively influencing chromatin accessibility. Members of Ets, Runx and TCF/Lef TF families occupied the vast majority of accessible chromatin regions, acting as 'housekeepers', 'universal amplifiers' and 'placeholders', respectively, at sites that maintained or gained accessibility upon T cell activation. In addition, a small subset of strongly induced immune response genes displayed a noncanonical TF recruitment pattern. Our study provides a key resource and foundation for the understanding of transcriptional and epigenetic regulation in T cells and offers a new perspective on the hierarchical interactions between critical TFs.
The crystal structure of nucleotide-free yeast F1 ATPase has been determined at a resolution of 3.6 Å. The overall structure is very similar to that of the ground state enzyme. In particular, the βDP ...and βTP subunits both adopt the closed conformation found in the ground state structure despite the absence of bound nucleotides. This implies that interactions between the γ and β subunits are as important as nucleotide occupancy in determining the conformational state of the β subunits. Furthermore, this result suggests that for the mitochondrial enzyme, there is no state of nucleotide occupancy that would result in more than one of the β subunits adopting the open conformation. The adenine-binding pocket of the βTP subunit is disrupted in the apoenzyme, suggesting that the βDP subunit is responsible for unisite catalytic activity.
Sodium phenylbutyrate combined with taurursodiol reduces neuronal endoplasmic reticulum stress and mitochondrial dysfunction in experimental models. In a randomized trial, the combination slowed the ...rate of progression of ALS but did not affect the slow vital capacity or isometric muscle strength.
The structures and functions of the components of ATP synthases, especially those subunits involved directly in the catalytic formation of ATP, are widely conserved in metazoans, fungi, eubacteria, ...and plant chloroplasts. On the basis of a map at 32.5-Å resolution determined in situ in the mitochondria of Trypanosoma brucei by electron cryotomography, it has been proposed that the ATP synthase in this species has a noncanonical structure and different catalytic sites in which the catalytically essential arginine finger is provided not by the α-subunit adjacent to the catalytic nucleotide-binding site as in all species investigated to date, but rather by a protein, p18, found only in the euglenozoa. A crystal structure at 3.2-Å resolution of the catalytic domain of the same enzyme demonstrates that this proposal is incorrect. In many respects, the structure is similar to the structures of F₁-ATPases determined previously. The α₃β₃-spherical portion of the catalytic domain in which the three catalytic sites are found, plus the central stalk, are highly conserved, and the arginine finger is provided conventionally by the α-subunits adjacent to each of the three catalytic sites found in the β-subunits. Thus, the enzyme has a conventional catalytic mechanism. The structure differs from previous described structures by the presence of a p18 subunit, identified only in the euglenozoa, associated with the external surface of each of the three α-subunits, thereby elaborating the F₁-domain. Subunit p18 is a pentatricopeptide repeat (PPR) protein with three PPRs and appears to have no function in the catalytic mechanism of the enzyme.
Previously, we developed a 3-dimensional cell culture model of human tuberculosis (TB) and demonstrated its potential to interrogate the host-pathogen interaction (Tezera et al., 2017a). Here, we use ...the model to investigate mechanisms whereby immune checkpoint therapy for cancer paradoxically activates TB infection. In patients, PD-1 is expressed in
(Mtb)-infected lung tissue but is absent in areas of immunopathology. In the microsphere model, PD-1 ligands are up-regulated by infection, and the PD-1/PD-L1 axis is further induced by hypoxia. Inhibition of PD-1 signalling increases Mtb growth, and augments cytokine secretion. TNF-α is responsible for accelerated Mtb growth, and TNF-α neutralisation reverses augmented Mtb growth caused by anti-PD-1 treatment. In human TB, pulmonary TNF-α immunoreactivity is increased and circulating PD-1 expression negatively correlates with sputum TNF-α concentrations. Together, our findings demonstrate that PD-1 regulates the immune response in TB, and inhibition of PD-1 accelerates Mtb growth via excessive TNF-α secretion.
In 2016, the order
Mononegavirales
was emended through the addition of two new families (
Mymonaviridae
and
Sunviridae
), the elevation of the paramyxoviral subfamily
Pneumovirinae
to family status (
...Pneumoviridae
), the addition of five free-floating genera (
Anphevirus
,
Arlivirus
,
Chengtivirus
,
Crustavirus
, and
Wastrivirus
), and several other changes at the genus and species levels. This article presents the updated taxonomy of the order
Mononegavirales
as now accepted by the International Committee on Taxonomy of Viruses (ICTV).
Fibrotic disease is caused by the continuous deposition of extracellular matrix by persistently activated fibroblasts (also known as myofibroblasts), even after the resolution of the injury. Using ...fibroblasts from porcine aortic valves cultured on hydrogels that can be softened via exposure to ultraviolet light, here we show that increased extracellular stiffness activates the fibroblasts, and that cumulative tension on the nuclear membrane and increases in the activity of histone deacetylases transform transiently activated fibroblasts into myofibroblasts displaying condensed chromatin with genome-wide alterations. The condensed structure of the myofibroblasts is associated with cytoskeletal stability, as indicated by the inhibition of chromatin condensation and myofibroblast persistence after detachment of the nucleus from the cytoskeleton via the displacement of endogenous nesprins from the nuclear envelope. We also show that the chromatin structure of myofibroblasts from patients with aortic valve stenosis is more condensed than that of myofibroblasts from healthy donors. Our findings suggest that nuclear mechanosensing drives distinct chromatin signatures in persistently activated fibroblasts.
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