A longstanding mystery has been the absence of cytoplasmic intermediate filaments (IFs) from Drosophila despite their importance in other organisms. In the course of characterizing the in vivo expression and functions of Drosophila Tropomyosin (Tm) isoforms, we discovered an essential but unusual product of the Tm1 locus, Tm1-I/C, which resembles an IF protein in some respects. Like IFs, Tm1-I/C spontaneously forms filaments in vitro that are intermediate in diameter between F-actin and microtubules. Like IFs but unlike canonical Tms, Tm1-I/C contains N- and C-terminal low-complexity domains flanking a central coiled coil. In vivo, Tm1-I/C forms cytoplasmic filaments that do not associate with F-actin or canonical Tms. Tm1-I/C is essential for collective border cell migration, in epithelial cells for proper cytoarchitecture, and in the germline for the formation of germ plasm. These results suggest that flies have evolved a distinctive type of cytoskeletal filament from Tm.

Low-mass "dwarf" galaxies represent the most significant challenges to the cold dark matter (CDM) model of cosmological structure formation. Because these faint galaxies are (best) observed within the Local Group (LG) of the Milky Way (MW) and Andromeda (M31), understanding their formation in such an environment is critical. We present first results from the Latte Project: the Milky Way on Feedback in Realistic Environments (FIRE). This simulation models the formation of an MW-mass galaxy to z = 0 within ACDM cosmology, including dark matter, gas, and stars at unprecedented resolution: baryon particle mass of 7070 M⊙ with gas kernel/softening that adapts down to 1 pc (with a median of 25-60 pc at z = 0). Latte was simulated using the GIZMO code with a mesh-free method for accurate hydrodynamics and the FIRE-2 model for star formation and explicit feedback within a multi-phase interstellar medium. For the first time, Latte self-consistently resolves the spatial scales corresponding to half-light radii of dwarf galaxies that form around an MW-mass host down to Mstar ≳ 10 M⊙ .Lattes population of dwarf galaxies agrees with the LG across a broad range of properties: (1) distributions of stellar masses and stellar velocity dispersions (dynamical masses), including their joint relation; (2) the mass- metallicity relation; and (3) diverse range of star formation histories, including their mass dependence. Thus, Latte produces a realistic population of dwarf galaxies at Mstar ≳ 10 M⊙. that does not suffer from the "missing satellites" or "too big to fail" problems of small-scale structure formation. We conclude that baryonic physics can reconcile observed dwarf galaxies with standard ACDM cosmology.

In patients with premotor Huntington's disease (pmHD), literature has reported decreases in caudate volume. However, the regional vulnerability of the caudate nucleus to pmHD remains to be clarified. We aimed to determine whether regional structural damage of the caudate nucleus was present in pmHD and was correlated with clinical profile using a surface-based morphometric technique applied to T1-weighted MRI. The study cohort consisted of 14 volunteers with genetically confirmed pmHD (6 males; 41.8 ± 13.2 years) and 11 age- and sex-matched controls (5 males; 46.2 ± 11.9 years, p > 0.3). On 3-T T1-weighted images, bilateral caudate volumes were manually delineated. The resulting labels were converted to a surface, triangulated with 1002 points equally distributed across subjects using SPHARM-PDM. Displacement vectors were then computed between each individual and a template surface representing the whole cohort. Computing point-wise Jacobian determinants (JD) from these vectors quantified local volumes. We found decreases in bilateral global caudate volumes in the pmHD group compared to controls (t = 3.4; p = 0.002). Point-wise analysis of local volumes mapped caudate atrophy in pmHD primarily onto medial surface (t > 2.7; FDR < 0.05), with most pronounced changes in anteromedial subdivision. In a combined group of patients and controls, volume within the area presenting significant group difference was positively correlated with scores of executive function (r = 0.7; p < 0.001) and working memory (r = 0.6; p = 0.002). In patients, the caudate atrophy was associated with increase in disease burden (r = 0.7; p = 0.005). Caudate subnuclear atrophy measured using our surface-based morphometric technique is evident in pmHD, correlates with clinical variables, and may provide a more sensitive biomarker than global volumes.

We report the formation of bound star clusters in a sample of high-resolution cosmological zoom-in simulations of z ≥ 5 galaxies from the Feedback In Realistic Environments project. We find that bound clusters preferentially form in high-pressure clouds with gas surface densities over 104M⊙ pc-2, where the cloud-scale star formation efficiency is near unity and young stars born in these regions are gravitationally bound at birth. These high-pressure clouds are compressed by feedback-driven winds and/or collisions of smaller clouds/gas streams in highly gas-rich, turbulent environments. The newly formed clusters follow a power-law mass function of dN/dM ~ M-2. The cluster formation efficiency is similar across galaxies with stellarmasses of~107-1010M⊙ at z ≥ 5. The age spread of cluster stars is typically a few Myr and increases with cluster mass. The metallicity dispersion of cluster members is ~0.08 dex in [Z/H] and does not depend on clustermass significantly. Our findings support the scenario that present-day old globular clusters (GCs) were formed during relatively normal star formation in high-redshift galaxies. Simulations with a stricter/looser star formation model form a factor of a few more/fewer bound clusters per stellar mass formed, while the shape of the mass function is unchanged. Simulations with a lower local star formation efficiency form more stars in bound clusters. The simulated clusters are larger than observed GCs due to finite resolution. Our simulations are among the first cosmological simulations that form bound clusters self-consistently in a wide range of high-redshift galaxies.

Using a state-of-the-art cosmological simulation of merging proto-galaxies at high redshift from the FIRE project, with explicit treatments of star formation and stellar feedback in the interstellar medium, we investigate the formation of star clusters and examine one of the formation hypotheses of present-day metal-poor globular clusters. We find that frequent mergers in high-redshift proto-galaxies could provide a fertile environment to produce long-lasting bound star clusters. The violent merger event disturbs the gravitational potential and pushes a large gas mass of ≳ 105-6M⊙ collectively to high density, at which point it rapidly turns into stars before stellar feedback can stop star formation. The high dynamic range of the reported simulation is critical in realizing such dense star-forming clouds with a small dynamical time-scale, tff ≲ 3 Myr, shorter than most stellar feedback time-scales. Our simulation then allows us to trace how clusters could become virialized and tightly bound to survive for up to ~420 Myr till the end of the simulation. Because the cluster's tightly bound core was formed in one short burst, and the nearby older stars originally grouped with the cluster tend to be preferentially removed, at the end of the simulation the cluster has a small age spread.

Background

With organismal aging, the hypothalamic-pituitary-gonadal (HPG) activity gradually decreases, resulting in the systemic functional declines of the target tissues including skeletal muscles. Although the HPG axis plays an important role in health span, how the HPG axis systemically prevents functional aging is largely unknown.

Methods

We generated muscle stem cell (MuSC)-specific androgen receptor (Ar) and oestrogen receptor 2 (Esr2) double knockout (dKO) mice and pharmacologically inhibited (Antide) the HPG axis to mimic decreased serum levels of sex steroid hormones in aged mice. After short-term and long-term sex hormone signalling ablation, the MuSCs were functionally analysed, and their aging phenotypes were compared with those of geriatric mice (30-month-old). To investigate pathways associated with sex hormone signalling disruption, RNA sequencing and bioinformatic analyses were performed.

Results

Disrupting the HPG axis results in impaired muscle regeneration [wild-type (WT) vs. dKO, P < 0.0001; Veh vs. Antide, P = 0.004]. The expression of DNA damage marker (in WT = 7.0 ± 1.6%, dKO = 32.5 ± 2.6%, P < 0.01; in Veh = 13.4 ± 4.5%, Antide = 29.7 ± 5.5%, P = 0.028) and senescence-associated β-galactosidase activity (in WT = 3.8 ± 1.2%, dKO = 10.3 ± 1.6%, P < 0.01; in Veh = 2.1 ± 0.4%, Antide = 9.6 ± 0.8%, P = 0.005), as well as the expression levels of senescence-associated genes, p16^Ink4a and p21^Cip1 , was significantly increased in the MuSCs, indicating that genetic and pharmacological inhibition of the HPG axis recapitulates the progressive aging process of MuSCs. Mechanistically, the ablation of sex hormone signalling reduced the expression of transcription factor EB (Tfeb) and Tfeb target gene in MuSCs, suggesting that sex hormones directly induce the expression of Tfeb, a master regulator of the autophagy-lysosome pathway, and consequently autophagosome clearance. Transduction of the Tfeb in naturally aged MuSCs increased muscle mass [control geriatric MuSC transplanted tibialis anterior (TA) muscle = 34.3 ± 2.9 mg, Tfeb-transducing geriatric MuSC transplanted TA muscle = 44.7 ± 6.7 mg, P = 0.015] and regenerating myofibre size [eMyHC⁺ tdTomato⁺ myofibre cross-section area (CSA) in control vs. Tfeb, P = 0.002] after muscle injury.

Conclusions

Our data show that the HPG axis systemically controls autophagosome clearance in MuSCs through Tfeb and prevents MuSCs from senescence, suggesting that sustained HPG activity throughout life regulates autophagosome clearance to maintain the quiescence of MuSCs by preventing senescence until advanced age.

Two dimensional (2D) materials have found various applications because of their unique physical properties. For example, graphene has been used as the electron transparent membrane for liquid cell transmission electron microscopy (TEM) due to its high mechanical strength and flexibility, single-atom thickness, chemical inertness, etc. Here, we report using 2D MoS₂ as a functional substrate as well as the membrane window for liquid cell TEM, which is enabled by our facile and polymer-free MoS₂ transfer process. This provides the opportunity to investigate the growth of Pt nanocrystals on MoS₂ substrates, which elucidates the formation mechanisms of such heterostructured 2D materials. We find that Pt nanocrystals formed in MoS₂ liquid cells have a strong tendency to align their crystal lattice with that of MoS₂, suggesting a van der Waals epitaxial relationship. Importantly, we can study its impact on the kinetics of the nanocrystal formation. The development of MoS₂ liquid cells will allow further study of various liquid phenomena on MoS₂, and the polymer-free MoS₂ transfer process will be implemented in a wide range of applications.

The dynamin GTPase is known to bundle actin filaments, but the underlying molecular mechanism and physiological relevance remain unclear. Our genetic analyses revealed a function of dynamin in propelling invasive membrane protrusions during myoblast fusion in vivo. Using biochemistry, total internal reflection fluorescence microscopy, electron microscopy and cryo-electron tomography, we show that dynamin bundles actin while forming a helical structure. At its full capacity, each dynamin helix captures 12-16 actin filaments on the outer rim of the helix. GTP hydrolysis by dynamin triggers disassembly of fully assembled dynamin helices, releasing free dynamin dimers/tetramers and facilitating Arp2/3-mediated branched actin polymerization. The assembly/disassembly cycles of dynamin promote continuous actin bundling to generate mechanically stiff actin super-bundles. Super-resolution and immunogold platinum replica electron microscopy revealed dynamin along actin bundles at the fusogenic synapse. These findings implicate dynamin as a unique multifilament actin-bundling protein that regulates the dynamics and mechanical strength of the actin cytoskeletal network.

Several lines of argument support the existence of a link between activity at the nuclei of galaxies, in the form of an accreting supermassive black hole, and star formation activity in these galaxies. Radio jets have long been argued to be an ideal mechanism that allows active galactic nuclei (AGNs) to interact with their host galaxies and affect star formation. We use a sample of radio sources in the North Ecliptic Pole (NEP) field to study the nature of this putative link, by means of spectral energy distribution (SED) fitting. We employ the excellent spectral coverage of the AKARI infrared space telescope and the rich ancillary data available in the NEP to build SEDs extending from UV to far-IR wavelengths. We find a significant AGN component in our sample of relatively faint radio sources (