In the nearly 80 years since catalytic hydroformylation was first reported, hundreds of billions of pounds of aldehyde have been produced by this atom efficient one-carbon homologation of alkenes in the presence of H2 and CO. Despite the economy and demonstrated scalability of hydroformylation, the enantioselective process (asymmetric hydroformylation, AHF) currently does not contribute significantly to the production of chiral aldehydes and their derivatives. Current impediments to practical application of AHF include low diversity of chiral ligands that provide effective rates and selectivities, limited exploration of substrate scope, few demonstrations of efficient flow reactor processes, and incomplete mechanistic understanding of the factors that control reaction selectivity and rate. This Account summarizes developments in ligand design, substrate scope, reactor technology, and mechanistic understanding that advance AHF toward practical and atom-efficient production of chiral α-stereogenic aldehydes. Initial applications of AHF were limited to activated terminal alkenes such as styrene, but recent developments enable high selectivity for unactivated olefins and more complex substrates such as 1,1'- and 1,2-disubstituted alkenes. Expanded substrate scope primarily results from new chiral phosphine ligands, especially phospholanes and bisdiazaphospholanes (BDPs). These ligands are now more accessible due to improved synthesis and resolution procedures. One of the virtues of diazaphospholanes is the relative ease of derivatization, including attachment to heterogeneous supports. Hydroformylation involves toxic and flammable reactants, a serious concern in pharmaceutical production facilities. Flow reactors offer many process benefits for handling dangerous reagents and for systematically moving from research to production scales. New approaches to achieving good gas-liquid mixing in flow reactors have been demonstrated with BDP-derived catalyst systems and lend assurance that AHF can be practically implemented by the pharmaceutical and fine chemical industries. To date, progress in AHF has been empirically driven, because hydroformylation is a complex, multistep process for which the origins of chemo-, regio-, and enantioselectivity are difficult to elucidate. Mechanistic complexity arises from three concurrent catalytic cycles (linear and two diastereomeric branched paths), significant pooling of catalyst as off-cycle species, and multiple elementary steps that are kinetically competitive. Addressing such complexity requires new approaches to collecting kinetic and extra-kinetic information and analyzing these data. In this Account, we describe our group's progress toward understanding the complex kinetics and mechanism of AHF as catalyzed by rhodium bis(diazaphospholane) catalysts. Our strategy features both "outside-in" (i.e., monitoring catalytic rates and selectivities as a function of reactant concentration and temperature) and "inside-out" (i.e., building kinetic models based on the rates of component steps of the catalytic reaction) approaches. These studies include isotopic labeling, interception and characterization of catalytic intermediates using NMR techniques, multinuclear high-pressure NMR spectroscopy, and sophisticated kinetic modeling. Such broad-based approaches illuminate the kinetic and mechanistic origins of selectivity and activity of AHF and the elucidation of important principles that apply to all catalytic reactions.

Acute heart failure (AHF) is a clinical syndrome with devastating prognosis. Despite considerable improvements in the treatment of chronic heart failure, most trials of new drugs for AHF, such as vasodilators, inotropes, and diuretics, have failed to show a prognostic benefit. Therefore, pharmacological treatment of AHF has changed very little, and loop diuretics have remained a cornerstone drug for decades. One of the emerging factors possibly playing an important role in AHF management is the time course of treatment. Several recent retrospective studies have highlighted the importance of early treatment in AHF; however, at the time, support from a prospective study with an adequate number of enrolled patients was lacking. The Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure (REALITY-AHF) was the first prospective study to specifically focus on the time course of treatment in the very acute phase and its prognostic implication in patients with AHF. Data from the REALITY-AHF revealed that early treatment with intravenous furosemide is significantly associated with lower in-hospital mortality. Although pathophysiological background of this association remains to be investigated, the time course of treatment may be a critical component of AHF treatment, and it will be important to take this factor into account in future clinical studies on AHF.

Like several other arthropod species, stick insects use their antennae for tactile exploration of the near-range environment and for spatial localisation of touched objects. More specifically, Carausius morosus continuously moves its antennae during locomotion and reliably responds to antennal contact events with directed movements of a front leg. Here we investigate the afferent projection patterns of antennal hair fields (aHF), proprioceptors known to encode antennal posture and movement, and to be involved in antennal movement control. We show that afferents of all seven aHF of C. morosus have terminal arborisations in the dorsal lobe (DL) of the cerebral (=supraoesophageal) ganglion, and descending collaterals that terminate in a characteristic part of the gnathal (=suboesophageal) ganglion. Despite differences of functional roles among aHF, terminal arborisation patterns show no topological arrangement according to segment specificity or direction of movement. In the DL, antennal motoneuron neurites show arborizations in proximity to aHF afferent terminals. Despite the morphological similarity of single mechanoreceptors of aHF and adjacent tactile hairs on the pedicel and flagellum, we find a clear separation of proprioceptive and exteroceptive mechanosensory neuropils in the cerebral ganglion. Moreover, we also find this functional separation in the gnathal ganglion.

The syndrome viral haemorrhagic fever (VHF) designates a broad range of diseases that are caused by different viruses including members of the family Arenaviridae. Prophylaxis for Argentine Haemorrhagic Fever (AHF), caused by the arenavirus Junín (JUNV), has been achieved by the use of a live attenuated vaccine, named Candid#1. The standard treatment of AHF is transfusion of convalescent human plasma. Our aim was to develop an alternative and safer treatment for AHF based on the use of virus-neutralizing single domain antibodies (VHHs). We describe the first reported VHHs directed against an arenavirus. These VHHs could neutralize Candid#1 by altering virion binding/fusion. Surprisingly, the neutralizing VHHs appeared to be specific for the viral nucleoprotein (N) that is not known to be involved in arenavirus entry. Candid#1 VHH-escape viruses had acquired a predicted N-glycosylation site in the surface glycoprotein GP1 that is present in highly pathogenic JUNV strains. Accordingly, the Candid#1-neutralizing VHHs could not neutralize pathogenic JUNV strains, but they could still bind to cells infected with a pathogenic strain or the escape mutant viruses. These results show that the attenuated strains of JUNV can be potently neutralized by nucleoprotein-specific VHHs.

The review underlines that advanced heart failure (AHF) patients who experience sustained cardiac recovery in the current left ventricular assist device (LVAD) era have similar clinical characteristics to those who experienced myocardial recovery in the pre-LVAD era. They are young, do not have coronary artery disease and were treated for idiopathic dilated cardiomyopathy within weeks to months of experiencing symptoms. As recently shown with progressive remodeling of the transverse tubular system, AHF results in myocyte and extracellular matrix alterations that with time become irreversible. Young age, short duration of symptoms and LV systolic dysfunction as evidenced by smaller LV cavity dimension are primary determinants of sustained cardiac recovery in patients with AHF. Mechanical circulatory support can be life saving in patients with low-cardiac output and end-organ dysfunction. However, the underlying condition and not mechanical circulatory support appears to be the primary determinant of sustained myocardial recovery.