Apoptotic cell-based therapies against transplant rejection: role of recipient’s dendritic cells

One of the ultimate goals in transplantation is to develop novel therapeutic methods for induction of donor-specific tolerance to reduce the side effects caused by the generalized immunosuppression associated to the currently used pharmacologic regimens. Interaction or phagocytosis of cells in early apoptosis exerts potent anti-inflammatory and immunosuppressive effects on antigen (Ag)-presenting cells (APC) like dendritic cells (DC) and macrophages. This observation led to the idea that apoptotic cell-based therapies could be employed to deliver donor-Ag in combination with regulatory signals to recipient’s APC as therapeutic approach to restrain the anti-donor response. This review describes the multiple mechanisms by which apoptotic cells down-modulate the immuno-stimulatory and pro-inflammatory functions of DC and macrophages, and the role of the interaction between apoptotic cells and APC in self-tolerance and in apoptotic cell-based therapies to prevent/treat allograft rejection and graft-versus-host disease in murine experimental systems and in humans. It also explores the role that in vivo-generated apoptotic cells could have in the beneficial effects of extracorporeal photopheresis, donor-specific transfusion, and tolerogenic DC-based therapies in transplantation

Psychological Aspects of Bariatric Surgery as a Treatment for Obesity

PURPOSE OF REVIEW: Little is known about the psychological effects on life after bariatric surgery despite the high prevalence of psychological disorders in candidates seeking this procedure. Our review discusses the literature around the psychological impact of bariatric surgery, exploring whether the procedure addresses underlying psychological conditions that can lead to morbid obesity and the effect on eating behaviour postoperatively.RECENT FINDINGS: Findings show that despite undisputed significant weight loss and improvements in comorbidities, current literature suggests some persisting disorder in psychological outcomes like depression and body image for patients at longer term follow-up, compared to control groups. Lack of postoperative psychological monitoring and theoretical mapping limits our understanding of reasons behind these findings. Reframing bariatric approaches to morbid obesity to incorporate psychological experience postoperatively would facilitate understanding of psychological aspects of bariatric surgery and how this surgical treatment maps onto the disease trajectory of obesity

More Than Smell - COVID-19 Is Associated With Severe Impairment of Smell,Taste, and Chemesthesis

Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change +/- 100) revealed a mean reduction of smell (-79.7 +/- 28.7, mean +/- standard deviation), taste (-69.0 +/- 32.6), and chemesthetic (-37.3 +/- 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis.The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms

Two-dimensional electronic spectroscopy as a tool for tracking molecular conformations in DNA/RNA aggregates

A computational strategy to simulate two-dimensional electronic spectra (2DES) is introduced, which allows us to analyse ground state dynamics and to sample and measure different conformations attained by flexible molecular systems in solution. An explicit mixed quantum mechanics/molecular mechanics (QM/MM) approach is employed for the evaluation of the necessary electronic excited state energies and transition dipole moments. The method is applied towards a study of the highly flexible water-solvated adenine-adenine monophosphate (ApA), a system featuring two interacting adenine moieties that display various intermolecular arrangements, known to deeply affect their photochemical outcome. Molecular dynamics simulations and cluster analysis have been used to select the molecular conformations, reducing the complexity of the flexible ApA conformational space. By using our sum-over-states (SOS) approach to obtain the 2DES spectra for each of these selected conformations, we can discern spectral changes and relate them to specific nuclear arrangements: close lying π-stacked bases exhibit a splitting of their respective1Lasignal traces; T-stacked bases exhibit the appearance of charge transfer states in the low-energy Vis probing window while displaying no1Lasplitting, being particularly favoured when promoting amino to 5-ring interactions; unstacked and distant adenine moieties exhibit signals similar to those of the adenine monomer, as is expected for non-interacting nucleobases. 2DES maps reveal the spectral fingerprints associated with specific molecular conformations, and are thus a promising option to enable their quantitative spectroscopic detection beyond standard 1D pump-probe techniques. This is expected to aid the understanding of how nucleobase aggregation controls and modulates the photostability and photo-damage of extended DNA/RNA systems

The highly excited-state manifold of guanine: calibration for nonlinear electronic spectroscopy simulations

A computational protocol based on the complete and restricted active space self-consistent field (CASSCF/RASSCF) methods and their second-order perturbation theory extensions (CASPT2/RASPT2) is employed to benchmark the highly excited-state manifold of the DNA/RNA canonical purine nucleobase guanine in vacuo. Several RASPT2 schemes are tested, displaying a steady convergence of electronic transition energies and dipole moments upon active space enlargement toward the reference values. The outcome allows calibrating and optimizing computational efforts by considering cheaper and more approximate RAS schemes that could enable the characterization of the excited-state manifolds of multi-chromophoric systems, such as DNA/RNA nucleobase dimers or multimers. Simulations of two-dimensional electronic spectra show similar trends to those observed on the other purine nucleobase adenine, deviating from this and other pyrimidine nucleobases in featuring its main excited-state absorption signal, embodied by sizable double HOMO to LUMO excitation contributions, in the UV probing window

Photophysics of deoxycytidine and 5-methyldeoxycytidine in solution: a comprehensive picture by quantum mechanical calculations and femtosecond fluorescence spectroscopy

The study concerns the relaxation of electronic excited states of the DNA nucleoside deoxycytidine (dCyd) and its methylated analogue 5-methyldeoxycytidine (5mdCyd), known to be involved in the formation of UV-induced lesions of the genetic code. Due to the existence of four closely lying and potentially coupled excited states, the deactivation pathways in these systems are particularly complex and have not been assessed so far. Here, we provide a complete mechanistic picture of the excited state relaxation of dCyd/5mdCyd in three solvents—water, acetonitrile, and tetrahydrofuran—by combining femtosecond fluorescence experiments, addressing the effect of solvent proticity on the relaxation dynamics of dCyd and 5mdCyd for the first time, and two complementary quantum mechanical approaches (CASPT2/MM and PCM/TD-CAM-B3LYP). The lowest energy ππ* state is responsible for the sub-picosecond lifetime observed for dCyd in all the solvents. In addition, computed excited state absorption and transient IR spectra allow one, for the first time, to assign the tens of picoseconds time constant, reported previously, to a dark state (nOπ*) involving the carbonyl lone pair. A second low-lying dark state, involving the nitrogen lone pair (nNπ*), does significantly participate in the excited state dynamics. The 267 nm excitation of dCyd leads to a non-negligible population of the second bright ππ* state, which affects the dynamics, acting mainly as a “doorway” state for the nOπ* state. The solvent plays a key role governing the interplay between the different excited states; unexpectedly, water favors population of the dark states. In the case of 5mdCyd, an energy barrier present on the main nonradiative decay route explains the 6-fold lengthening of the excited state lifetime compared to that of dCyd, observed for all the examined solvents. Moreover, C5-methylation destabilizes both nOπ* and nNπ* dark states, thus preventing them from being populated