Browse Articles

Multicentre case-control study on the association between COVID-19 vaccines and neurological disorders (COVIVAX)

An analysis of the cultivation, consumption and composition of home-grown cannabis following decriminalisation in the Australian Capital Territory

Plastic responses to past environments shape adaptation to novel selection pressures

Phenotypic plasticity may pave the way for rapid adaptation to newly encountered environments. Although it is often contested, there is growing evidence that initial plastic responses of ancestral populations to new environmental cues may promote subsequent adaptation. However, we do not know whether plasticity to cues present in the ancestral habitat (past-cue plasticity) can facilitate adaptation to novel cues. Conceivably, this could occur if plastic responses are coincidentally optimal to both past and novel cues (i.e., are preadaptive) or if they are transferred to novel cues during adaptation. Past plastic phenotype values could also become fixed during adaptation to the new environment. To uncover the role of past-cue plasticity in adaptation, we tested gene expression plasticity responses of two parallel mine-waste-adapted Silene uniflora populations and their closest coastal relatives. Plants were exposed to the past and novel cues of salt and zinc, which revealed that during adaptation to mine waste, plasticity to salt diminishes. Despite this, our results show that ancestral plasticity to salt has a substantial impact on subsequent adaptation to zinc. For a third of genes that have evolved zinc plasticity in mine populations, salt plasticity has been transferred to the zinc response. Furthermore, a quarter of fixed expression differences between mine and coastal populations were similar to ancestral salt responses. Alongside evidence that ancestral plasticity to novel cues can facilitate adaptation, our results provide a clear indication that ancestral past-cue plasticity can also play a key role in rapid, parallel adaptation to novel habitats.

Chest CT characterization of children with necrotizing pneumonia due to Mycoplasma pneumoniae infection

Optimal strategies for correcting merotelic chromosome attachments in anaphase

Accurate chromosome segregation in mitosis depends on proper connections of sister chromatids, through microtubules, to the opposite poles of the early mitotic spindle. Transiently, many inaccurate connections are formed and rapidly corrected throughout the mitotic stages, but a small number of merotelic connections, in which a chromatid is connected to both spindle poles, remain lagging at the spindle’s equator in anaphase. Most of the lagging chromatids are eventually moved to one or the other pole, likely by a combination of microtubules’ turnover and the brute force of pulling by the microtubules’ majority from the one pole against the microtubules’ minority from the other pole. We use computer simulations from two stochastic models (1D and full 3D CellDynaMo model) combining force balances and microtubules’ dynamics for the lagging chromatids to investigate what maximizes the percentage of segregated laggards. We find that a) brute force tug-of-war with slow (< 0.0001 s −1 ) microtubules’ detachment rate can move asymmetric laggards to the poles in limited time, b) rapid (> 0.01 s −1 ) microtubules’ detachment rate leads to a significant loss of the laggards, and c) intermediate (~ 0.001 s −1 ) microtubules’ detachment rate ensures higher than 90% accuracy of segregation. The simulations also shed light on the waiting time required to correct the merotelic errors in anaphase and on the roles of chromatid-attached microtubule number and Aurora B–mediated, spatially graded regulation of microtubule kinetics in anaphase.

Prevalence and associated factors of epiretinal membrane using spectralis OCT in Fujian Eye Study

Errors are robustly tamed in cumulative knowledge processes

As knowledge accumulates in science and society in a distributed fashion, erroneous derivations can be introduced into the corpus of knowledge. Such derivations can compromise the validity of any units of knowledge that rely on them in the future. Can societal knowledge maintain some level of integrity given simple distributed error-checking mechanisms? In this paper, we investigate the following formulation of the question: assuming that a constant fraction of the new derivations is wrong, is it possible for simple error-checking mechanisms that apply when a new unit of knowledge is derived to maintain the integrity of the corpus of knowledge? This question was introduced by Ben-Eliezer et al. [“Is this correct? Let’s check!” in 14th Innovations in Theoretical Computer Science Conference (ITCS, 2023)], who gave a robust affirmative answer in a specific probabilistic model for knowledge accumulation. Namely, this model required that new units depend on just one existing unit and join the process according to a preferential attachment rule. In this work, we consider much more general families of processes of knowledge accumulation, where new units may depend on multiple existing units and join according to varied attachment mechanisms. We also consider models with a (random) fraction of insertions of adversarial nodes. We give a robust affirmative answer to the above question by showing that for all of these models, as long as many of the units follow simple local heuristics for checking a bounded number of units they depend on, all errors will be eventually eliminated.

Nonlinear relationship between hepatic steatosis index and reversion to normal glucose regulation in Chinese adults with prediabetes

Design of a light and Ca ²⁺ switchable organic–peptide hybrid

The design of organic–peptide hybrids has the potential to combine our vast knowledge of protein design with small molecule engineering to create hybrid structures with complex functions. Here, we describe the computational design of a photoswitchable Ca 2+ -binding organic–peptide hybrid. The designed molecule, designated Ca 2+ -binding switch (CaBS), combines an EF-hand motif from classical Ca 2+ -binding proteins such as calmodulin with a photoswitchable group that can be reversibly isomerized between a spiropyran (SP) and merocyanine (MC) state in response to different wavelengths of light. The MC/SP group acts both as a photoswitch as well as an optical sensor of Ca 2+ binding. Photoconversion of the SP to the corresponding MC unmasks an acidic phenol, which CaBS uses as an integral part of both its Ca 2+ -binding site as well as its tertiary and quaternary structure. By design, the SP state of CaBS is monomeric, while the Ca 2+ -bound form of the MC state is an obligate dimer, with two Ca 2+ -binding sites formed at the interface of a domain-swapped dimer. Thus, light and Ca 2+ were expected to serve as an “AND gate” that powers a change in backbone structure/dynamics, oligomerization state, and fluorescence properties of the designed molecule. CaBS was designed using Rosetta and molecular dynamics simulations, and experimentally characterized by nuclear magnetic resonance, isothermal titration calorimetry, and optical titrations. These data illustrate the potential of combining small molecule engineering with de novo protein design to develop sensors whose conformation, association state, and optical properties respond to multiple environmental cues.

N-Cadherin based adhesion and Rac1 activity regulate tension polarization in the actin cortex

Integrative bioinformatic approach reveals novel melatonin-related biomarkers for Alzheimer’s disease

Establishment and application of a zebrafish model of Werner syndrome identifies sapanisertib as a potential antiaging drug

Aging is a complex process that affects multiple organs, and the discovery of a pharmacological approach to ameliorate aging is considered the Holy Grail of medicine. Here, we performed an N-ethyl-N-nitrosourea forward genetic screening in zebrafish and identified an accelerated aging mutant named meteor ( met ), harboring a mutation in the Werner syndrome RecQ - like helicase ( wrn ) gene. Loss of wrn leads to a short lifespan and age-related characteristics in the intestine of zebrafish embryos, such as cellular senescence, genomic instability, and epigenetic alteration. Therefore, we conducted a screening of antiaging drugs using the met mutant and revealed that sapanisertib effectively ameliorated most of the aging phenotypes of the mutant. Mechanistically, the geroprotective effects of sapanisertib may be attributed to inhibition of mTORC1/2. Furthermore, sapanisertib also attenuated chronological aging in wild-type aged zebrafish and replicative-senescence in human foreskin fibroblasts. Taken together, our study introduces a unique and efficient model for large-scale antiaging drug screening in vertebrates and suggests sapanisertib as a potential therapeutic option for treating premature aging and promoting healthy aging.

PET imaging of AAV9 and AAVBR1 trafficking in normal mice

Natural variations in <i>TT8</i> and its neighboring <i>STK</i> confer yellow seed with elevated oil content in <i>Brassica juncea</i>

Seed color is a critical quality trait in numerous plant species. In oilseed Brassica crops, including rapeseed and mustard, yellow seeds are distinguished by their significantly higher oil content and faster germination rates compared to black or brown counterparts. Despite the agronomic significance of the yellow seeds being a prime breeding target, the mechanisms underlying elevated oil content remain obscure. In this study, we assembled the first telomere-to-telomere (T2T) genome of B. juncea and further investigated the genetic regulation, molecular mechanism, and the evolutionary history of yellow seeds in B. juncea. Through an analysis of allelic variation in the TRANSPARENT TESTA 8 ( TT8 ) genes across 1,002 worldwide B . juncea accessions, we traced the single origin of yellow seeds to approximately 2,300 y ago in Southwestern China. Furthermore, we discovered the MADS-box gene SEEDSTICK ( STK ) coevolved with TT8 , and they coordinately regulated seed size, oil accumulation, and seed coat proportion in B. juncea . These findings open broad avenues for targeted breeding of yellow-seeded Brassica crops with elevated oil content.

The occurrence characteristic and dissolution mechanism of lithium-rich sediments in Salt Lake Mahai of Qaidam Basin, NW China

Rational design and modular synthesis of biodegradable ionizable lipids via the Passerini reaction for mRNA delivery

The ionizable lipid component of lipid nanoparticle (LNP) formulations is essential for mRNA delivery by facilitating endosomal escape. Conventionally, these lipids are synthesized through complex, multistep chemical processes that are both time-consuming and require significant engineering. Furthermore, the development of new ionizable lipids is hindered by a limited understanding of the structure-activity relationships essential for effective mRNA delivery. In this work, we have developed a modular platform utilizing the Passerini reaction to rapidly generate large, chemically diverse libraries of biodegradable ionizable lipids. This high-throughput approach enables the systematic exploration of various lipid components–head groups, tails, and spacers–and their impacts on mRNA delivery efficiency. By investigating the hydrogen bonding potential between the lipid’s head groups and the mRNA’s ribose phosphate complex, we found that optimizing the methylene units between the lipid’s head groups and linkages could enhance endosomal escape and, consequently, mRNA delivery efficiencies. Leveraging this insight, our platform has led to the identification of the biodegradable ionizable lipid A4B4-S3, which outperforms the current clinical benchmark, SM-102, in gene editing efficacy in mouse liver following systemic administration and demonstrates the promise for repeat-dose protein replacement treatments. This work not only offers a rapid, scalable method for ionizable lipid synthesis but also deepens our understanding of their structure-activity relationships, paving the way for more effective mRNA therapeutics.

Author Correction: Sentiment analysis of the Hamas-Israel war on YouTube comments using deep learning

Impaired spatial coding of the hippocampus in a dentate gyrus hypoplasia mouse model

The hippocampal dentate gyrus (DG) is thought to orthogonalize inputs from the entorhinal cortex (pattern separation) and relay this information to the CA3 region. In turn, attractor dynamics in CA3 perform a pattern completion or error correction operation before sending its output to CA1. In a mouse model of congenital hypoplasia of the DG, a deficiency in the Wntless (Wls) gene, specifically in cells expressing Gfap-Cre , which targets neuronal progenitors, led to an almost total absence of dentate granule cells and modestly impaired performance in spatial tasks. Here, we investigated the physiological consequences of granule cell loss in these mice by conducting in vivo calcium imaging from CA1 principal cells during behavior. The spatial selectivity of these cells was preserved without the DG. On a linear track, place fields in mutant mice were more likely to be near track terminals and to encode the distance from the start point in each running direction. In an open box, CA1 cells in mutant mice exhibited reductions in the percentage of place cells, in spatial information, and in place field stability. The reduction in place field stability across repeated exposures to the same environment resulted in a reduction in the differential representations of two different contexts in mutant mice compared to wild-type mice. These results suggest that DG helps to stabilize CA1 spatial representations, especially in 2-D environments, and that the lack of stability across similar environments may play a key role in the deficits of animals with DG dysfunction in discriminating different environments.

A polysaccharide-based hydrogel platform for tumor spheroid production and anticancer drug screening

CBX2 suppresses interferon signaling to diminish tumor immunogenicity via a noncanonical corepressor complex

Chromobox 2 (CBX2), a crucial component of the polycomb repressive complex (PRC), has been implicated in the development of various human cancers. However, its role in the regulation of tumor immunogenicity and immune evasion remains inadequately understood. In this study, we found that ablation of CBX2 led to tumor growth inhibition, activation of the tumor immune microenvironment, and enhanced therapeutic efficacy of anti-PD1 or adoptive T cell therapies by using murine syngeneic tumor models. By analysis of the CBX2-regulated transcriptional program coupled with mass spectrometry screening of CBX2-interacting proteins, we found that CBX2 suppresses interferon signaling independent of its function in the canonical PRC. Mechanistically, CBX2 directly interacts with RACK1 and facilitates the recruitment of HDAC1, which attenuates the H3K27ac modification on the promoter regions of interferon-stimulated genes, thereby suppressing interferon signaling. Consequently, CBX2 reduces tumor immunogenicity and enables immune evasion. Moreover, a high expression level of CBX2 is associated with immune suppressive tumor microenvironment and reduced efficacy of immunotherapy across various human cancer types. Our study identifies a noncanonical CBX2–RACK1–HDAC1 corepressor complex in suppression of tumor immunogenicity, thereby presenting a potential target and biomarker for tumor immunotherapy.