Tau pathology is known to spread in a hierarchical pattern in Alzheimer's disease (AD) brain during disease progression, likely by trans-synaptic tau transfer between neurons. However, the tau ...species involved in inter-neuron propagation remains unclear. To identify tau species responsible for propagation, we examined uptake and propagation properties of different tau species derived from postmortem cortical extracts and brain interstitial fluid of tau-transgenic mice, as well as human AD cortices. Here we show that PBS-soluble phosphorylated high-molecular-weight (HMW) tau, though very low in abundance, is taken up, axonally transported, and passed on to synaptically connected neurons. Our findings suggest that a rare species of soluble phosphorylated HMW tau is the endogenous form of tau involved in propagation and could be a target for therapeutic intervention and biomarker development.
Soft robots possess many attributes that are difficult, if not impossible, to achieve with conventional robots composed of rigid materials. Yet, despite recent advances, soft robots must still be ...tethered to hard robotic control systems and power sources. New strategies for creating completely soft robots, including soft analogues of these crucial components, are needed to realize their full potential. Here we report the untethered operation of a robot composed solely of soft materials. The robot is controlled with microfluidic logic that autonomously regulates fluid flow and, hence, catalytic decomposition of an on-board monopropellant fuel supply. Gas generated from the fuel decomposition inflates fluidic networks downstream of the reaction sites, resulting in actuation. The body and microfluidic logic of the robot are fabricated using moulding and soft lithography, respectively, and the pneumatic actuator networks, on-board fuel reservoirs and catalytic reaction chambers needed for movement are patterned within the body via a multi-material, embedded 3D printing technique. The fluidic and elastomeric architectures required for function span several orders of magnitude from the microscale to the macroscale. Our integrated design and rapid fabrication approach enables the programmable assembly of multiple materials within this architecture, laying the foundation for completely soft, autonomous robots.
Successful emergence from the soil is essential for plant establishment in natural and farmed systems. It has been assumed that the absence of light in the soil is the preeminent signal perceived ...during early seedling development, leading to a distinct morphogenic plan (skotomorphogenesis) 1, characterized by traits providing an adaptive advantage until emergence and photomorphogenesis. These traits include suppressed chlorophyll synthesis, promotion of hypocotyl elongation, and formation of a closed apical hook that protects the stem cell niche from damage 2, 3. However, absence of light by itself is not a sufficient environmental signal for early seedling development 4, 5. Reduced oxygen levels (hypoxia) can occur in water-logged soils 6–8. We therefore hypothesized that below-ground hypoxia may be an important, but thus far undiscovered, ecological component regulating seedling development. Here, we show that survival and establishment of seedlings following darkness depend on their ability to sense hypoxia, through enhanced stability of group VII Ethylene Response Factor (ERFVII) transcription factors. Hypoxia is perceived as a positive environmental component in diverse taxa of flowering plants, promoting maintenance of skotomorphogenic traits. Hypoxia greatly enhances survival once light is perceived, while oxygen is necessary for the subsequent effective completion of photomorphogenesis. Together with light perception, oxygen sensing therefore allows an integrated response to the complex and changing physical microenvironment encountered during early seedling growth. We propose that plants monitor the soil’s gaseous environment after germination, using hypoxia as a key external cue to protect the stem cell niche, thus ensuring successful rapid establishment upon emergence above ground.
•Low oxygen (hypoxia) enhances seedling survival in the dark•Hypoxia is sensed by oxygen-mediated degradation of ERFVII transcription factors•Stable ERFVIIs enhance dark-activated development and repress light-activated development•Plants monitor the gaseous environment to coordinate photomorphogenesis
Abbas et al. demonstrate that hypoxia sensing is an important component of photomorphogenesis. Hypoxia acts as a positive external positional cue controlling morphogenetic and biochemical adaptations to protect the stem cell niche. Sensing hypoxia in the dark coordinates responses that maximize survival and establishment in the light.
The variant allele HLA‐B*15:02 is strongly associated with greater risk of Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients treated with carbamazepine or oxcarbazepine. ...The variant allele HLA‐A*31:01 is associated with greater risk of maculopapular exanthema, drug reaction with eosinophilia and systemic symptoms, and SJS/TEN in patients treated with carbamazepine. We summarize evidence from the published literature supporting these associations and provide recommendations for carbamazepine and oxcarbazepine use based on HLA genotypes.
Nitric oxide (NO) is an important signaling compound in prokaryotes and eukaryotes. In plants, NO regulates critical developmental transitions and stress responses. Here, we identify a mechanism for ...NO sensing that coordinates responses throughout development based on targeted degradation of plant-specific transcriptional regulators, the group VII ethylene response factors (ERFs). We show that the N-end rule pathway of targeted proteolysis targets these proteins for destruction in the presence of NO, and we establish them as critical regulators of diverse NO-regulated processes, including seed germination, stomatal closure, and hypocotyl elongation. Furthermore, we define the molecular mechanism for NO control of germination and crosstalk with abscisic acid (ABA) signaling through ERF-regulated expression of ABSCISIC ACID INSENSITIVE5 (ABI5). Our work demonstrates how NO sensing is integrated across multiple physiological processes by direct modulation of transcription factor stability and identifies group VII ERFs as central hubs for the perception of gaseous signals in plants.
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•We elucidate a general molecular mechanism for nitric oxide sensing in plants•Group VII ERFs act as nitric oxide sensors via the N-end rule pathway•Group VII ERFs are shown to mediate crosstalk between nitric oxide and abscisic acid•The N-end rule regulates nitric oxide homeostasis through group VII ERFs
Gibbs et al. report that NO-dependent degradation of group VII ERF transcription factors by the N-end rule pathway mediates NO sensing and signal transduction, identifying these transcription factors as central hubs for the perception of gaseous signals in plants.
Gram-negative bacteria have an outer membrane that serves as a barrier to noxious agents in the environment. This protective function is dependent on lipopolysaccharide, a large glycolipid located in ...the outer leaflet of the outer membrane. Lipopolysaccharide is synthesized at the cytoplasmic membrane and must be transported to the cell surface. To understand this transport process, we reconstituted membrane-to-membrane movement of lipopolysaccharide by incorporating purified inner and outer membrane transport complexes into separate proteoliposomes. Transport involved stable association between the inner and outer membrane proteoliposomes. Our results support a model in which lipopolysaccharide molecules are pushed one after the other in a PEZ dispenser-like manner across a protein bridge that connects the inner and outer membranes.
Meiotic recombination is an essential biological process that generates genetic diversity and ensures proper segregation of chromosomes during meiosis. From a large USDA dairy cattle pedigree with ...over half a million genotyped animals, we extracted 186,927 three-generation families, identified over 8.5 million maternal and paternal recombination events, and constructed sex-specific recombination maps for 59,309 autosomal SNPs. The recombination map spans for 25.5 Morgans in males and 23.2 Morgans in females, for a total studied region of 2,516 Mb (986 kb/cM in males and 1,085 kb/cM in females). The male map is 10% longer than the female map and the sex difference is most pronounced in the subtelomeric regions. We identified 1,792 male and 1,885 female putative recombination hotspots, with 720 hotspots shared between sexes. These hotspots encompass 3% of the genome but account for 25% of the genome-wide recombination events in both sexes. During the past forty years, males showed a decreasing trend in recombination rate that coincided with the artificial selection for milk production. Sex-specific GWAS analyses identified PRDM9 and CPLX1 to have significant effects on genome-wide recombination rate in both sexes. Two novel loci, NEK9 and REC114, were associated with recombination rate in both sexes, whereas three loci, MSH4, SMC3 and CEP55, affected recombination rate in females only. Among the multiple PRDM9 paralogues on the bovine genome, our GWAS of recombination hotspot usage together with linkage analysis identified the PRDM9 paralogue on chromosome 1 to be associated in the U.S. Holstein data. Given the largest sample size ever reported for such studies, our results reveal new insights into the understanding of cattle and mammalian recombination.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pseudo‐natural products (PNPs) combine natural product (NP) fragments in novel arrangements not accessible by current biosynthesis pathways. As such they can be regarded as non‐biogenic fusions of ...NP‐derived fragments. They inherit key biological characteristics of the guiding natural product, such as chemical and physiological properties, yet define small molecule chemotypes with unprecedented or unexpected bioactivity. We iterate the design principles underpinning PNP scaffolds and highlight their syntheses and biological investigations. We provide a cheminformatic analysis of PNP collections assessing their molecular properties and shape diversity. We propose and discuss how the iterative analysis of NP structure, design, synthesis, and biological evaluation of PNPs can be regarded as a human‐driven branch of the evolution of natural products, that is, a chemical evolution of natural product structure.
Pseudo‐natural products provide new opportunities in the discovery of bioactive small molecules and can be regarded as a human‐driven chemical evolution of natural product structure.
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