The Caenorhabditis elegans Kinesin-3 motor UNC-104/ KIF1A is degraded upon loss of specific binding to cargo

UNC-104/KIF1A is a Kinesin-3 motor that transports synaptic vesicles from the cell body towards the synapse by binding to PI(4,5)P(2) through its PH domain. The fate of the motor upon reaching the synapse is not known. We found that wild-type UNC-104 is degraded at synaptic regions through the ubiquitin pathway and is not retrogradely transported back to the cell body. As a possible means to regulate the motor, we tested the effect of cargo binding on UNC-104 levels. The unc-104(e1265) allele carries a point mutation (D1497N) in the PI(4,5)P(2) binding pocket of the PH domain, resulting in greatly reduced preferential binding to PI(4,5)P(2)in vitro and presence of very few motors on pre-synaptic vesicles in vivo. unc-104(e1265) animals have poor locomotion irrespective of in vivo PI(4,5)P(2) levels due to reduced anterograde transport. Moreover, they show highly reduced levels of UNC-104 in vivo. To confirm that loss of cargo binding specificity reduces motor levels, we isolated two intragenic suppressors with compensatory mutations within the PH domain. These show partial restoration of in vitro preferential PI(4,5)P(2) binding and presence of more motors on pre-synaptic vesicles in vivo. These animals show improved locomotion dependent on in vivo PI(4,5)P(2) levels, increased anterograde transport, and partial restoration of UNC-104 protein levels in vivo. For further proof, we mutated a conserved residue in one suppressor background. The PH domain in this triple mutant lacked in vitro PI(4,5)P(2) binding specificity, and the animals again showed locomotory defects and reduced motor levels. All allelic variants show increased UNC-104 levels upon blocking the ubiquitin pathway. These data show that inability to bind cargo can target motors for degradation. In view of the observed degradation of the motor in synaptic regions, this further suggests that UNC-104 may get degraded at synapses upon release of cargo

Reducing Particle Size Enhances Chemical Treatment in Finishing Diets

Three hundred-sixty calf-fed steers were fed either treated or untreated corn stover that was previously ground through a 1-in or 3–in screen. Treated stover diets improved ADG and F:G compared to untreated. Reducing particle size improved ADG and F:G but did not influence DMI. Compared to a control diet with 5% roughage and 15 percentage units more corn, diets with 20% treated corn stover had similar F:G, ADG, DMI, and carcass quality. Up to 15% additional corn can be replaced with treated corn stover when diets contain wet distillers grains, and may be further enhanced by reducing particle size before chemical treatment

Reducing Particle Size Enhances Chemical Treatment in Finishing Diets

Three hundred-sixty calf-fed steers were fed either treated or untreated corn stover that was previously ground through a 1-in or 3–in screen. Treated stover diets improved ADG and F:G compared to untreated. Reducing particle size improved ADG and F:G but did not influence DMI. Compared to a control diet with 5% roughage and 15 percentage units more corn, diets with 20% treated corn stover had similar F:G, ADG, DMI, and carcass quality. Up to 15% additional corn can be replaced with treated corn stover when diets contain wet distillers grains, and may be further enhanced by reducing particle size before chemical treatment

Perspective on Coarse-Graining, Cognitive Load, and Materials Simulation

The predictive capabilities of computational materials science today derive from overlapping advances in simulation tools, modeling techniques, and best practices. We outline this ecosystem of molecular simulations by explaining how important contributions in each of these areas have fed into each other. The combined output of these tools, techniques, and practices is the ability for researchers to advance understanding by efficiently combining simple models with powerful software. As specific examples, we show how the prediction of organic photovoltaic morphologies have improved by orders of magnitude over the last decade, and how the processing of reacting epoxy thermosets can now be investigated with million-particle models. We discuss these two materials systems and the training of materials simulators through the lens of cognitive load theory. For students, the broad view of ecosystem components should facilitate understanding how the key parts relate to each other first, followed by targeted exploration. In this way, the paper is organized in loose analogy to a coarse-grained model: The main components provide basic framing and accelerated sampling from which deeper research is better contextualized. For mentors, this paper is organized to provide a snapshot in time of the current simulation ecosystem and an on-ramp for simulation experts into the literature on pedagogical practice

Is voice a marker for autism spectrum disorder? A systematic review and meta-analysis

Individuals with Autism Spectrum Disorder (ASD) tend to show distinctive, atypical acoustic patterns of speech. These behaviours affect social interactions and social development and could represent a non-invasive marker for ASD. We systematically reviewed the literature quantifying acoustic patterns in ASD. Search terms were: (prosody OR intonation OR inflection OR intensity OR pitch OR fundamental frequency OR speech rate OR voice quality OR acoustic) AND (autis* OR Asperger). Results were filtered to include only: empirical studies quantifying acoustic features of vocal production in ASD, with a sample size > 2, and the inclusion of a neurotypical comparison group and/or correlations between acoustic measures and severity of clinical features. We identified 34 articles, including 30 univariate studies and 15 multivariate machine-learning studies. We performed metaanalyses of the univariate studies, identifying significant differences in mean pitch and pitch range between individuals with ASD and comparison participants (Cohen’s d of 0.4-0.5 and discriminatory accuracy of about 61-64%). The multivariate studies reported higher accuracies than the univariate studies (63-96%). However, the methods used and the acoustic features investigated were too diverse for performing meta-analysis. We conclude that multivariate studies of acoustic patterns are a promising but yet unsystematic avenue for establishing ASD markers. We outline three recommendations for future studies: open data, open methods, and theory-driven research

Long Astral Microtubules and RACK-1 Stabilize Polarity Domains during Maintenance Phase in Caenorhabditis elegans Embryos

Cell polarity is a very well conserved process important for cell differentiation, cell migration, and embryonic development. After the establishment of distinct cortical domains, polarity cues have to be stabilized and maintained within a fluid and dynamic membrane to achieve proper cell asymmetry. Microtubules have long been thought to deliver the signals required to polarize a cell. While previous studies suggest that microtubules play a key role in the establishment of polarity, the requirement of microtubules during maintenance phase remains unclear. In this study, we show that depletion of Caenorhabditis elegans RACK-1, which leads to short astral microtubules during prometaphase, specifically affects maintenance of cortical PAR domains and Dynamin localization. We then investigated the consequence of knocking down other factors that also abolish astral microtubule elongation during polarity maintenance phase. We found a correlation between short astral microtubules and the instability of PAR-6 and PAR-2 domains during maintenance phase. Our data support a necessary role for astral microtubules in the maintenance phase of cell polarity

Age at onset as stratifier in idiopathic Parkinson’s disease – effect of ageing and polygenic risk score on clinical phenotypes

Several phenotypic differences observed in Parkinson’s disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients

Forage Quality and Animal Performance of Steers Grazing Smooth Bromegrass/Legume Pastures

A trial was conducted to evaluate effects of interseeding legumes into smooth bromegrass pastures on animal performance and forage quality. Animal gains on legume/bromegrass treatments were higher than bromegrass alone. Laboratory analysis of diet samples collected from ruminally fistulated steers indicated no difference in the undegradable intake protein content of pastures. Legume/bromegrass treatments had higher IVDMD than the control. Therefore, the increases in gain are attributed to increased energy of legume/bromegrass diets and not undegradable protein content

Evaluation of Rumen Metabolism and Digestibility when Treated Crop Residues are Fed in Cattle Finishing Diets

A metabolism trial was conducted to evaluate rumen pH, digestibility, and ruminal VFA concentrations of steers fed 25% CaO treated or untreated cobs, wheat straw, and corn stover. Treated diets had greater digestibility of DM, OM, and NDF compared to untreated diets. Substituting 15 percentage units of corn and 10% roughage with 25 percentage units of 5% CaO treated cobs, wheat straw, or corn stover resulted in similar DM digestibility, rumen pH and VFA concentrations