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The ability of cytoskeletal motors to move unidirectionally along filamentous tracks is central to their role in cargo transport, motility and cell division. Kinesin and myosin motor families have a subclass that moves towards the opposite end of the microtubule or actin filament with respect to the rest of the motor family1,2, whereas all dynein motors that have been studied so far exclusively move towards the minus end of the microtubule3. Guided by cryo-electron microscopy and molecular dynamics simulations, we sought to understand the mechanism that underpins the directionality of dynein by engineering a Saccharomyces cerevisiae dynein that is directed towards the plus end of the microtubule. Here, using single-molecule assays, we show that elongation or shortening of the coiled-coil stalk that connects the motor to the microtubule controls the helical directionality of dynein around microtubules. By changing the length and angle of the stalk, we successfully reversed the motility towards the plus end of the microtubule. These modifications act by altering the direction in which the dynein linker swings relative to the microtubule, rather than by reversing the asymmetric unbinding of the motor from the microtubule. Because the length and angle of the dynein stalk are fully conserved among species, our findings provide an explanation for why all dyneins move towards the minus end of the microtubule.

Peripheral neuropathy (PN) is a prevalent and debilitating complication of obesity, prediabetes, and type 2 diabetes, which remains poorly understood and lacks disease-modifying therapies. Fortunately, diet and/or exercise have emerged as effective treatment strategies for PN. Here, we examined the impact of caloric restriction (CR) and high-intensity interval training (HIIT) interventions, alone or combined (HIIT-CR), on metabolic and PN outcomes in high-fat diet (HFD) mice. HFD feeding alone resulted in obesity, impaired glucose tolerance, and PN. Peripheral nerves isolated from these mice also developed insulin resistance (IR). CR and HIIT-CR, but not HIIT alone, improved HFD-induced metabolic dysfunction. However, all interventions improved PN to similar extents. When examining the underlying neuroprotective mechanisms in whole nerves, we found that CR and HIIT-CR activate the fuel-sensing enzyme AMPK. We then performed complimentary in vitro work in Schwann cells, the glia of peripheral nerves. Treating primary Schwann cells with the saturated fatty acid palmitate to mimic prediabetic conditions caused IR, which was reversed by the AMPK activator, AICAR. Together, these results enhance our understanding of PN pathogenesis, the differential mechanisms by which diet and exercise may improve PN, and Schwann cell-specific contributions to nerve insulin signaling and PN progression. Article Highlights: Diet and exercise are recommended for treating peripheral neuropathy in prediabetes. To identify the optimal regimen and the underlying neuroprotective mechanisms, we compared the effects of caloric restriction (CR), high-intensity interval training (HIIT), and their combination (HIIT-CR), on metabolic and neuropathy outcomes following high-fat diet feeding. While all interventions improved neuropathy, CR and HIIT-CR, but not HIIT alone, improved metabolic profiles and promoted insulin sensitivity in peripheral nerves of high-fat diet–fed mice. In vitro, palmitate-treated Schwann cells developed insulin resistance, which was reversed by AMPK activation. CR, alone or combined with HIIT, ameliorates neuropathy by restoring nerve insulin sensitivity. [ABSTRACT FROM AUTHOR]

We examine the bunching behaviour of individuals in Australia in response to an extra 15 per cent tax on compulsory retirement contributions imposed on those earning more than $ A250,000. We find almost no bunching by wage and salary earners. There is extensive bunching by those with business or trust income. For this group, we estimate an elasticity of taxable income of 0.027. Females and older workers are more likely to bunch. The results suggest that the tax induces a tax planning response but little labour supply response. [ABSTRACT FROM AUTHOR]

Background: A promising method for improving physical inactivity among women is to increase their engagement in group-based exercise programs. Fitness communities are exercise groups that practice the principles of group dynamics and promote a lifestyle of physical activity by engaging members through social media and hosting social event/hangouts outside of the gym or "fitness" setting. Purpose: The purpose of this study was to examine the role of "fitness communities" as a mechanism for increasing engagement in physical activity. Methods: In-depth, semi-structured interviews (N = 15) from women who were members of an established fitness community (i.e. Titan Fitness; the original name has been changed for purposes of anonymity) in Southern California. Results: Results suggested that the women's experiences in Titan Fitness were encompassed by six sub-themes which were the following: "Structured Exercise Classes with Group Dynamics": (1) personal and group accountability and (2) minimizing intimidation; "Social Media Engagement": (3) empowerment and (4) accountability via online engagement; and "Engagement Outside of the Physical Gym Setting": (5) in-group engagement and (6) out-group (extended) engagement. Discussion: Our findings illustrated that community members that were engaged in all three components of a fitness community described improved physical activity adherence. Translation to Health Practice: These findings may benefit fitness professionals, researchers, and Health Education practitioners who desire to develop innovative theoretically-based interventions for women having difficulty with physical activity adherence.

In Figure 1c of the original article, ARP1 was incorrectly labelled as ARP11. The highlight for reference 37 was mistakenly placed under reference 36 and the highlight for reference 29 should have also referred to reference 16 (instead of 19). The HTML and PDF versions of the article have now been corrected.

Cytoplasmic dynein 1 is an important microtubule-based motor in many eukaryotic cells. Dynein has critical roles both in interphase and during cell division. Here, we focus on interphase cargoes of dynein, which include membrane-bound organelles, RNAs, protein complexes and viruses. A central challenge in the field is to understand how a single motor can transport such a diverse array of cargoes and how this process is regulated. The molecular basis by which each cargo is linked to dynein and its cofactor dynactin has started to emerge. Of particular importance for this process is a set of coiled-coil proteins - activating adaptors - that both recruit dynein-dynactin to their cargoes and activate dynein motility.

Cytoplasmic dyneins are motor proteins in the AAA+ superfamily that transport cellular cargos toward microtubule minus-ends. Recently, ciliobrevins were reported as selective cell-permeable inhibitors of cytoplasmic dyneins. As is often true for first-in-class inhibitors, the use of ciliobrevins has in part been limited by low potency. Moreover, suboptimal chemical properties, such as the potential to isomerize, have hindered efforts to improve ciliobrevins. Here, we characterized the structure of ciliobrevins and designed conformationally constrained isosteres. These studies identified dynapyrazoles, inhibitors more potent than ciliobrevins. At single-digit micromolar concentrations dynapyrazoles block intraflagellar transport in the cilium and lysosome motility in the cytoplasm, processes that depend on cytoplasmic dyneins. Further, we find that while ciliobrevins inhibit both dynein's microtubule-stimulated and basal ATPase activity, dynapyrazoles strongly block only microtubule-stimulated activity. Together, our studies suggest that chemical-structure-based analyses can lead to inhibitors with improved properties and distinct modes of inhibition.

The Endangered Species Act (ESA) provides legal protection to imperiled populations and their associated habitats. As a part of this process, listed species must undergo a general status review (also called 5‐Year Review) to assess the progress toward recovery every 5 years. However, almost all 5‐year reviews result in a status of "no change," prompting scientists to question if the review process is robust enough to detect changes in recovery. The U.S. Fish and Wildlife Service (USFWS) was therefore interested in developing a standardized metric for monitoring more nuanced recovery progress as part of the status review. In collaboration with the USFWS, over 75 biologists from five different organizations developed and tested a set of novel metrics to summarize recovery progress of listed species by considering current and future conditions, threats, and conservation measures. We found that, although the majority of species had reviews with a recommendation of no change, scorers were able to use the metrics to interpret more nuanced changes in the 3Rs (resiliency, redundancy, and representation), threats, and conservation measures than in the status review. Our results suggest that these metrics could illuminate more nuanced areas of recovery and decline in species' conditions, but consistency among scorers and status reports should be a focus of future development. Our approach offers a rigorous set of metrics to systematically track the recovery progress of all ESA species. [ABSTRACT FROM AUTHOR]

The evolution of arc‐continent collision between the Palawan microcontinental block and the Cagayan Ridge in the southeastern margin of the South China Sea (SCS) is vital to understand how this collision correlated with seafloor spreading of the SCS. To address the evolution of arc‐continent collision, we studied the biostratigraphy and provenance of syn‐collisional sediments in the Isugod Basin in central‐southern Palawan. Microfossil analysis indicates a Late Miocene age (11.5–5.6 Ma) for the Isugod and Alfonso XIII Formations and rapid subsidence during initiation of the basin which may have been triggered by local extensional collapse of the wedge in response to forearc uplift. Multidisciplinary provenance analysis reveals that the Isugod and Alfonso XIII Formations were derived from the Middle Eocene–lower Oligocene Panas‐Pandian Formation on the Palawan wedge and the Late Eocene Central Palawan Ophiolite. These results suggest the emergence of both the orogenic wedge and obducted forearc ophiolite at ∼11.5 Ma, implying collision onset before ∼11.5 Ma. The collision initiation in Palawan could be better constrained to ∼18 Ma, based on the drowning of the Nido carbonate platform in the foreland. Therefore, the gravitational collapse of the Palawan wedge and the subsidence/formation of the Isugod Basin might reflect a significant uplift pulse in the hinterland of the wedge beginning within 13.4–11.5 Ma in the late stage of collision. It indicates that although compression originated from spreading of the SCS had ceased at 16–15 Ma, arc‐continent collision in Palawan did not stop and was sustained by compression from the upper plate afterward. Plain Language Summary: The Palawan microcontinental block is a continental fragment separated from the South China margin along with the seafloor spreading of the South China Sea (SCS). It finally collided with the Cagayan Ridge volcanic arc because of southward subduction of the Proto‐SCS. Therefore, precisely constraining the evolution of arc‐continent collision could help us to understand its association with the ending of the SCS spreading. To constrain the evolution of arc‐continent collision, we determined the depositional age and source of syn‐collisional sediments in the Isugod Basin in central‐southern Palawan. Our results shows that the Isugod Basin sediments were deposited during the Late Miocene (11.5–5.6 Ma) following local gravitational collapse of the Palawan orogenic wedge driven by uplift and oversteepening. Isugod Basin sediments were eroded from both the orogenic wedge and obducted forearc ophiolite that were uplifted and exposed subaerially, indicating collision began before ∼11.5 Ma. As the onset of collision could be constrained to ∼18 Ma, we propose a significant uplift pulse in the hinterland of the wedge began at 13.4–11.5 Ma in the late stage of collision. This further indicates that arc‐continent collision in Palawan did not stop although compression derived from spreading of the SCS had ceased at 16–15 Ma. Key Points: Sediments in the Isugod Basin were deposited at 11.5–5.6 Ma following local gravitational collapse of the Palawan wedge driven by upliftThe Isugod Basin sediments were supplied by erosion of the Palawan wedge and obducted forearc ophiolite exposed subaerially since ∼11.5 MaOnset of Palawan arc‐continent collision at ∼18 Ma followed by a significant uplift pulse in the Palawan wedge beginning within 13.4–11.5 Ma [ABSTRACT FROM AUTHOR]