Enantioselective Total Synthesis of (+)-Psiguadial B

The first enantioselective total synthesis of the cytotoxic natural product (+)-psiguadial B is reported. Key features of the synthesis include (1) the enantioselective preparation of a key cyclobutane intermediate by a tandem Wolff rearrangement/asymmetric ketene addition, (2) a directed C(sp^3)–H alkenylation reaction to strategically forge the C1–C2 bond, and (3) a ring-closing metathesis to build the bridging bicyclo[4.3.1]decane terpene framework

A modular approach to prepare enantioenriched cyclobutanes: synthesis of (+)-rumphellaone A

A modular synthesis of enantioenriched polyfunctionalized cyclobutanes was developed that features an 8-aminoquinolinamide directed C–H arylation reaction. The C–H arylation products were derivatized through subsequent decarboxylative coupling processes. This synthetic strategy enabled a 9-step enantioselective total synthesis of the antiproliferative meroterpenoid (+)-rumphellaone A

Validity of energy expenditure estimation methods during 10 days of military training

Wearable physical activity (PA) monitors have improved the ability to estimate free-living total energy expenditure (TEE) but their application during arduous military training alongside more well-established research methods has not been widely documented. This study aimed to assess the validity of two wrist-worn activity monitors and a PA log against doubly-labelled water (DLW) during British Army Officer Cadet (OC) training. For 10 days of training, twenty (10 male and 10 female) OCs (mean ± SD: age 23 ± 2 years, height 1.74 ± 0.09 m, body mass 77.0 ± 9.3 kg) wore one research-grade accelerometer (GENEActiv, Cambridge, UK) on the dominant wrist, wore one commercially-available monitor (Fitbit SURGE, USA) on the non-dominant wrist and completed a self-report PA log. Immediately prior to this 10-day period, participants consumed a bolus of DLW and provided daily urine samples, which were analysed by mass spectrometry to determine TEE. Bivariate correlations and limits of agreement (LoA) were employed to compare TEE from each estimation method to DLW. Average daily TEE from DLW was 4112 ± 652 kcal·day against which the GENEActiv showed near identical average TEE (mean bias ± LoA: -15 ± 851 kcal day ) while Fitbit tended to underestimate (-656 ± 683 kcal·day ) and the PA log substantially overestimate (+1946 ± 1637 kcal·day ). Wearable physical activity monitors provide a cheaper and more practical method for estimating free-living TEE than DLW in military settings. The GENEActiv accelerometer demonstrated good validity for assessing daily TEE and would appear suitable for use in large-scale, longitudinal military studies

A modular approach to prepare enantioenriched cyclobutanes: synthesis of (+)-rumphellaone A

A modular synthesis of enantioenriched polyfunctionalized cyclobutanes was developed that features an 8-aminoquinolinamide directed C–H arylation reaction. The C–H arylation products were derivatized through subsequent decarboxylative coupling processes. This synthetic strategy enabled a 9-step enantioselective total synthesis of the antiproliferative meroterpenoid (+)-rumphellaone A

Evolution of a Strategy for the Enantioselective Total Synthesis of (+)-Psiguadial B

(+)-Psiguadial B is a diformyl phloroglucinol meroterpenoid that exhibits antiproliferative activity against the HepG2 human hepatoma cancer cell line. This full account details the evolution of a strategy that culminated in the first enantioselective total synthesis of (+)-psiguadial B. A key feature of the synthesis is the construction of the trans-cyclobutane motif by a Wolff rearrangement with in situ catalytic, asymmetric trapping of the ketene. An investigation of the substrate scope of this method to prepare enantioenriched 8-aminoquinolinamides is disclosed. Three routes toward (+)-psiguadial B were evaluated that featured the following key steps: (1) an ortho-quinone methide hetero-Diels–Alder cycloaddition to prepare the chroman framework, (2) a Prins cyclization to form the bridging bicyclo[4.3.1]decane system, and (3) a modified Norrish–Yang cyclization to generate the chroman. Ultimately, the successful strategy employed a ring-closing metathesis to form the seven-membered ring and an intramolecular O-arylation reaction to complete the polycyclic framework of the natural product

Actin/microtubule crosstalk during platelet biogenesis in mice is critically regulated by Twinfilin1 and Cofilin1

Rearrangements of the microtubule (MT) and actin cytoskeleton are pivotal for platelet biogenesis. Hence, defects in actin- or MT-regulatory proteins are associated with platelet disorders in humans and mice. Previous studies in mice revealed that loss of the actin-depolymerizing factor homology (ADF-H) protein Cofilin1 (Cof1) in megakaryocytes (MKs) results in a moderate macrothrombocytopenia but normal MK numbers, whereas deficiency in another ADF-H protein, Twinfilin1 (Twf1), does not affect platelet production or function. However, recent studies in yeast have indicated a critical synergism between Twf1 and Cof1 in the regulation of actin dynamics. We therefore investigated platelet biogenesis and function in mice lacking both Twf1 and Cof1 in the MK lineage. In contrast to single deficiency in either protein, Twf1/Cof1 double deficiency (DKO) resulted in a severe macrothrombocytopenia and dramatically increased MK numbers in bone marrow and spleen. DKO MKs exhibited defective proplatelet formation in vitro and in vivo as well as impaired spreading and altered assembly of podosome-like structures on collagen and fibrinogen in vitro. These defects were associated with aberrant F-actin accumulation and, remarkably, the formation of hyperstable MT, which appears to be caused by dysregulation of the actin- and MT-binding proteins mDia1 and adenomatous polyposis coli. Surprisingly, the mild functional defects described for Cof1-deficient platelets were only slightly aggravated in DKO platelets suggesting that both proteins are largely dispensable for platelet function in the peripheral blood. In summary, these findings reveal critical redundant functions of Cof1 and Twf1 in ensuring balanced actin/microtubule crosstalk during thrombopoiesis in mice and possibly humans.Peer reviewe