Geometry sensing by dendritic cells dictates spatial organization and PGE2-induced dissolution of podosomes

Assembly and disassembly of adhesion structures such as focal adhesions (FAs) and podosomes regulate cell adhesion and differentiation. On antigen-presenting dendritic cells (DCs), acquisition of a migratory and immunostimulatory phenotype depends on podosome dissolution by prostaglandin E2 (PGE2). Whereas the effects of physico-chemical and topographical cues have been extensively studied on FAs, little is known about how podosomes respond to these signals. Here, we show that, unlike for FAs, podosome formation is not controlled by substrate physico-chemical properties. We demonstrate that cell adhesion is the only prerequisite for podosome formation and that substrate availability dictates podosome density. Interestingly, we show that DCs sense 3-dimensional (3-D) geometry by aligning podosomes along the edges of 3-D micropatterned surfaces. Finally, whereas on a 2-dimensional (2-D) surface PGE2 causes a rapid increase in activated RhoA levels leading to fast podosome dissolution, 3-D geometric cues prevent PGE2-mediated RhoA activation resulting in impaired podosome dissolution even after prolonged stimulation. Our findings indicate that 2-D and 3-D geometric cues control the spatial organization of podosomes. More importantly, our studies demonstrate the importance of substrate dimensionality in regulating podosome dissolution and suggest that substrate dimensionality plays an important role in controlling DC activation, a key process in initiating immune responses

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Thermochemistry of molybdenum tricarbonyl complexes of arenes and cyclic polyolefins

The heats of reaction of arene, cycloheptatriene, and cyclooctatetraene complexes of molybdenum tricarbonyl with pyridine yielding (py) 3Mo(CO) 3 have been measured by solution calorimetry. Reaction of toluene molybdenum tricarbonyl with cyclopentadiene yielding HMo(CO) 3C 5H 5 and with tetrahydrofuran yielding (THF) 3Mo(CO) 3 have also been studied thermochemically. These measurements yield accurate values for the enthalpy of arene exchange in methylene chloride solution for a number of organomolybdenum complexes. The order of stability: benzene < toluene < cyclooctatetraene < mesitylene < hexamethylbenzene < cycloheptatriene < (tris)-tetrahydrofuran < η 5-cyclopentadienylhydrido < (tris)-pyridine spans a range of 31 kcal/mol. The enthalpy of isomerization of cycloheptatriene to toluene is reduced by 7.1 ± 1.2 kcal/mol upon coordination to molybdenum tricarbonyl, indicative of a loss of “resonance” energy for the complexed arene. The MoH bond strength in HMo(CO) 3C 5H 5 is estimated as 66 ± 8 kcal/mol. The importance of entropic factors in arene exchange is discussed

Thermodynamic and kinetic studies of stable low valent transition metal radical complexes

The majority of stable low valent transition metal organometallic complexes obey the familiar eighteen-electron rule. Oxidative addition reactions of these complexes normally proceed by initial generation of sixteen electron coordinatively unsaturated species. Low valent 17 electron transition metal radical complexes ML n can be generated thermally or photochemically. Since radical recombination to form metal-metal bonded dimers L n MML n is a rapid process, the absolute concentration of metal radicals that can be achieved in solution is normally quite low. In cases where either there is no stable metal–metal bonded dimer or the metalmetal bond is so weak that the complex is completely dissociated in solution, relatively high concentrations (ca. 1 mM) are readily achieved. Illustrative mechanisms for oxidative addition reactions of ML n are discussed with a focus on reaction mechanisms that are second order in total metal concentration

The heats of reaction of phosphines and phosphites with toluene-molybdenum tricarbonyl : importance of both steric and electronic factors in determining the Mo-PR3 bond strength

The heats of reaction of tolueneMo(CO) 3 with a series of phosphines and phosphites have been measured by solution calorimetry. The order of stability toward formation of fac-(PR 3) 3Mo(CO) 3 in THF solution is: P(OCH 3) 3s > PMe 3 > P nBu 3 > PMe 2Ph > PEt 3 > triphos > P(OPh) 3 > PMePh 2 > PPh 3 > PCl 3 and spans a range of 25 kcal/mol reflecting individual bond strength differences up to 8 kcal/mol. The bulky phosphines PCy 3 and P tBu 3 react with tolueneMo(CO) 3 in THF, but 30–40 kcal/mol less heat is evolved in these reactions than with the other phosphines and phosphites. The coordinately unsaturated five-coordinate complexes (PR 3) 2Mo(CO) 3 are proposed as the reaction products. The importance of both steric and electronic factors in the MoP bond is discussed

ChemInform Abstract: SYNTHESIS AND REACTIONS OF THE TRANSITION METAL SUBSTITUTED TIN HYDRIDE HSN(MO(CO)3C5H5)3

Reaction of HMo(CO) 3C 5H 5 and Sn(C 5H 5) 2 produces the tin hydride HSn[Mo(CO) 3C 5H 5] 3 (I). Reaction of I with CCl 4, CHCl 3, or CH 2Cl 2 gives ClSn[Mo(CO) 3C 5H 5] 3 (II). With hydrogen chloride the hydride I reacts to produce the dichloride Cl 2Sn[Mo(CO) 3C 5H 5] 2. The first step in this reaction is cleavage of the SnH bond to produce the chloride II. The hydride I reacts with acetic acid to produce the diacetate (CH 3COO) 2Sn[Mo(CO) 3C 5H 5] 2