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Distinguishing strains by these criteria has become routine in rodent models, while identification of strains in natural hosts is more challenging and less reliable. [...]the overall ability to identify unique strains is limited because of the inability of current techniques to determine the detailed 3-dimensional features of each PrPSc variant. [...]damage at different brain regions by different prion strains provides a rationale to explain the distinct clinical signs routinely observed in laboratory settings. The strain phenomenon beyond the realm of prion diseases Several other diseases associated with protein misfolding have been shown to progress following prion-like mechanisms. [...]prion-like properties have been tested for non-PrPSc protein aggregates. For A[Beta], the fate of the aggregates generated in mice by exogenous “seeding” depends on both the seeds administered and the host [20]. [...]conformationally different aggregates from synthetic fibrils and deposits isolated from patients were propagated in the brains of transgenic mice expressing human A[Beta] [21,22].

The role of macrophages during regeneration in zebrafish has been well-documented. Nevertheless, new evidence indicates that zebrafish macrophages are a heterogeneous population of cells, and that they can play different roles during immune responses and in tissue restoration after damage and infection. In this work, we first aimed to classify zebrafish macrophages according to their distribution in the larva during homeostasis and after tissue damage, distinguishing peripheral, and hematopoietic tissue resident macrophages. We discovered differences between the migratory behavior of these two macrophage populations both before and after tissue damage, triggered by the amputation of the tail fin. Further, we found a specific role for peripheral tissue-resident macrophages, and we propose that these cells contribute to tail fin regeneration by down-regulating inflammatory mediators such as interleukin-1b ( ) and by diminishing reactive oxygen species (ROS) in the damage site. Our work suggests that specific macrophage populations recruited after tissue damage in zebrafish larvae can display different functions during both inflammation and tissue regeneration.

Many insect pests have developed resistance to existing chemical insecticides and consequently there is much interest in the development of new insecticidal compounds with novel modes of action. Although spiders have deployed insecticidal toxins in their venoms for over 250 million years, there is no evolutionary selection pressure on these toxins to possess oral activity since they are injected into prey and predators via a hypodermic needle-like fang. Thus, it has been assumed that spider-venom peptides are not orally active and are therefore unlikely to be useful insecticides. Contrary to this dogma, we show that it is possible to isolate spider-venom peptides with high levels of oral insecticidal activity by directly screening for per os toxicity. Using this approach, we isolated a 34-residue orally active insecticidal peptide (OAIP-1) from venom of the Australian tarantula Selenotypus plumipes. The oral LD50 for OAIP-1 in the agronomically important cotton bollworm Helicoverpa armigera was 104.2±0.6 pmol/g, which is the highest per os activity reported to date for an insecticidal venom peptide. OAIP-1 is equipotent with synthetic pyrethroids and it acts synergistically with neonicotinoid insecticides. The three-dimensional structure of OAIP-1 determined using NMR spectroscopy revealed that the three disulfide bonds form an inhibitor cystine knot motif; this structural motif provides the peptide with a high level of biological stability that probably contributes to its oral activity. OAIP-1 is likely to be synergized by the gut-lytic activity of the Bacillus thuringiensis Cry toxin (Bt) expressed in insect-resistant transgenic crops, and consequently it might be a good candidate for trait stacking with Bt.

  [...]a wide variety of misfolded structures are formed, ranging from small soluble oligomers to large fibrillar deposits. Since nuclei are formed, the aggregation increases in an exponential manner from small oligomers to fibers.

Sex in crocodilians is not determined by chromosomes, but by egg incubation temperature, where different temperatures produce different clutch sex ratios. Two patterns have been proposed to describe these changes in sex ratios: a 100% female proportion at low and high temperatures with male predominance at intermediate ones (FMF) or a simpler pattern with a single female‐to‐male transition (FM). Over the last three decades, researchers have provided empirical information to support either of these two patterns in different species; however, no consensus has been reached partly because data have not been analysed as a whole. Here, we aimed at gathering the existing data on these patterns to provide models of temperature‐dependent sex determination in those crocodilians studied so far. Potentially relevant publications were searched on Web of Knowledge, Scopus, Scielo and Science Direct. Studies that reported results on the sexual identity of crocodilian hatchlings obtained from constant temperature incubation treatments were considered. Using statistical models varying in their underlying assumptions, we evaluated which sex‐determination pattern was best supported for the studied crocodilians and constructed species‐specific and latitude‐specific models. Based on the 8,458 sexed hatchlings studied throughout 31 studies, we show that the evidence supports a shared FMF pattern in all the crocodilian species for which enough data are available. We find that such pattern changes between species and at different latitudes. These results suggest a lability of the FMF crocodilian sex‐determination pattern, a key feature under the present climate change scenario. This is the first time, after more than three decades of research, that an effort is made to gather the existing data on the temperature‐dependent sex determination in Crocodylia in order to derive unified patterns.

Cnidarians are one of the oldest known animal lineages (ca. 700 million years), with a unique envenomation apparatus to deliver a potent mixture of peptides and proteins. Some peptide toxins from cnidarian venom have proven therapeutic potential. Here, we use a transcriptomic/proteomic strategy to identify sequences with similarity to known venom protein families in the tentacles of the endemic Australian ‘speckled anemone’ (Oulactis sp.). Illumina RNASeq data were assembled de novo. Annotated sequences in the library were verified by cross-referencing individuals’ transcriptomes or protein expression evidence from LC-MS/MS data. Sequences include pore-forming toxins, phospholipases, peptidases, neurotoxins (sodium and potassium channel modulators), cysteine-rich secretory proteins and defensins (antimicrobial peptides). Fewer than 4% of the sequences in the library occurred across the three individuals examined, demonstrating high sequence variability of an individual’s arsenal. We searched for actinoporins in Oulactis sp. to assess sequence similarity to the only described toxins (OR-A and -G) for this genus and examined the domain architecture of venom-related peptides and proteins. The novel putative actinoporin of Oulactis sp. has a greater similarity to other species in the Actiniidae family than to O. orientalis. Venom-related sequences have an architecture that occurs in single, repeat or multi-domain combinations of venom-related (e.g. ShK-like) and non-venom (e.g. whey acid protein) domains. This study has produced the first transcriptomes for an endemic Australian sea anemone species and the genus Oulactis, while identifying nearly 400 novel venom-related peptides and proteins for future structural and functional analyses and venom evolution studies.

The intestinal barrier is composed of a complex cell network defining highly compartmentalized and specialized structures. Here, we use spatial transcriptomics to define how the transcriptomic landscape is spatially organized in the steady state and healing murine colon. At steady state conditions, we demonstrate a previously unappreciated molecular regionalization of the colon, which dramatically changes during mucosal healing. Here, we identified spatially-organized transcriptional programs defining compartmentalized mucosal healing, and regions with dominant wired pathways. Furthermore, we showed that decreased p53 activation defined areas with increased presence of proliferating epithelial stem cells. Finally, we mapped transcriptomics modules associated with human diseases demonstrating the translational potential of our dataset. Overall, we provide a publicly available resource defining principles of transcriptomic regionalization of the colon during mucosal healing and a framework to develop and progress further hypotheses. The colon is comprised of specialized cells that interact with each other to function, however, the molecular regionalization of the colon is incompletely understood. Here, the authors use spatial transcriptomics to generate a publicly available resource defining the transcriptomic regionalization of the colon during steady state and mucosal healing.

Monoclonal antibodies (mAbs) are one of the most successful and versatile protein-based pharmaceutical products used to treat multiple pathological conditions. The remarkable specificity of mAbs and their affinity for biological targets has led to the implementation of mAbs in the therapeutic regime of oncogenic, chronic inflammatory, cardiovascular, and infectious diseases. Thus, the discovery of novel mAbs with defined functional activities is of crucial importance to expand our ability to address current and future clinical challenges. In vitro, antigen-driven affinity selection employing phage display biopanning is a commonly used technique to isolate mAbs. The success of biopanning is dependent on the quality and the presentation format of the antigen, which is critical when isolating mAbs against membrane protein targets. Here, we provide a comprehensive investigation of two established panning strategies, surface-tethering of a recombinant extracellular domain and cell-based biopanning, to examine the impact of antigen presentation on selection outcomes with regards to the isolation of positive mAbs with functional potential against a proof-of-concept type I cell surface receptor. Based on the higher sequence diversity of the resulting antibody repertoire, presentation of a type I membrane protein in soluble form was more advantageous over presentation in cell-based format. Our results will contribute to inform and guide future antibody discovery campaigns against cell surface proteins.

In recent years, there has been a surge in the development of methods for cell segmentation and tracking, with initiatives like the Cell Tracking Challenge driving progress in the field. Most studies focus on regular cell population videos in which cells are segmented and followed, and parental relationships annotated. However, DNA damage induced by genotoxic drugs or ionizing radiation produces additional abnormal events since it leads to behaviors like abnormal cell divisions (resulting in a number of daughters different from two) and cell death. With this in mind, we developed an automatic mitosis classifier to categorize small mitosis image sequences centered around one cell as “Normal” or “Abnormal.” These mitosis sequences were extracted from videos of cell populations exposed to varying levels of radiation that affect the cell cycle’s development. We explored several deep-learning architectures and found that a network with a ResNet50 backbone and including a Long Short-Term Memory (LSTM) layer produced the best results (mean F1-score: 0.93 ± 0.06). In the future, we plan to integrate this classifier with cell segmentation and tracking to build phylogenetic trees of the population after genomic stress.