Biology Open最新文献

RUNX1::RUNX1T1 (R::RT1) acute myeloid leukaemia (AML) remains a clinical challenge, and further research is required to model and understand leukaemogenesis. Previous zebrafish R::RT1 models were hampered by embryonic lethality and low penetrance of the malignant phenotype. Here, we overcome this by developing an adult zebrafish model in which the human R::RT1 isoform 9a is co-expressed with the frequently co-occurring oncogenic NRASG12D mutation in haematopoietic stem and progenitor cells (HSPCs), using the Runx1+23 enhancer. Approximately 50% of F0 9a+NRASG12D transgenic zebrafish developed signs of haematological disease between 5 and 14 months, with 27% exhibiting AML-like pathology: myeloid precursor expansion, erythrocyte reduction, kidney marrow hypercellularity and the presence of blasts. Moreover, only 9a+NRASG12D transplant recipients developed leukaemia with high rates of mortality within 40 days, inferring the presence of leukaemia stem cells. These leukaemic features were rare or not observed in animals expressing either the NRAS or 9a oncogenes alone, suggesting 9a and NRAS cooperation drives leukaemogenesis. This novel adult AML zebrafish model provides a powerful new tool for investigating the basis of R::RT1 - NRAS cooperativity with the potential to uncover new therapeutic targets.

Students of biological allometry have used the logarithmic transformation for over a century to linearize bivariate distributions that are curvilinear on the arithmetic scale. When the distribution is linear, the equation for a straight line fitted to the distribution can be back-transformed to form a two-parameter power function for describing the original observations. However, many of the data in contemporary studies of allometry fail to meet the requirement for log-linearity, thereby precluding the use of the aforementioned protocol. Even when data are linear in logarithmic form, the two-parameter power equation estimated by back-transformation may yield a misleading or erroneous perception of pattern in the original distribution. A better approach to bivariate allometry would be to forego transformation altogether and to fit multiple models to untransformed observations by nonlinear regression, thereby creating a pool of candidate models with different functional form and different assumptions regarding random error. The best model in the pool of candidate models could then be identified by a selection procedure based on maximum likelihood. Two examples are presented to illustrate the power and versatility of newer methods for studying allometric variation. It always is better to examine the original data when it is possible to do so.

Mechanosensory hair cells located in the inner ear mediate the sensations of hearing and balance. If damaged, mammalian inner ear hair cells are unable to regenerate, resulting in permanent sensory deficits. Aquatic vertebrates like zebrafish (Danio rerio) have a specialized class of mechanosensory hair cells found in the lateral line system, allowing them to sense changes in water current. Unlike mammalian inner ear hair cells, lateral line hair cells can robustly regenerate following damage. In mammals, the transcription factor Foxg1 functions to promote normal development of the inner ear. Foxg1a is expressed in lateral line sensory organs in zebrafish larvae, but its function during lateral line development and regeneration has not been investigated. Our study demonstrates that mutation of foxg1a results in slower posterior lateral line primordium migration and delayed neuromast formation. In developing and regenerating neuromasts, we find that loss of Foxg1a function results in reduced hair cell numbers, as well as decreased proliferation of neuromast cells. Foxg1a specifically regulates the development and regeneration of Islet1-labeled hair cells. These data suggest that Foxg1 may be a valuable target for investigation of clinical hair cell regeneration.

As the demand for Octopus maya grows, sustainable farming practices become essential to prevent overexploitation, so that farming can be developed as a sustainable alternative to traditional fishing. Understanding the digestive dynamics of the octopus is essential for devising optimal dietary formulations in aquaculture. Despite the progress in understanding cephalopod digestion, little is known about the specific functioning of the digestive enzymes responsible for breaking down protein substrates. This knowledge gap underscores the need for further research to support sustainable O. maya population management. In this paper, dietary formulations are identified for cephalopods by characterizing O. maya digestive enzymes present in the digestive gland and gastric juice. The investigation revealed that acidic proteases showed a peak activity at higher temperatures than alkaline proteases. Inhibitors confirmed the presence of H, L, and D cathepsins. The lower activation energy of alkaline enzymes compared to acidic ones observed highlights an intriguing aspect of O. maya's digestive physiology. This research provides valuable insights into O. maya digestive enzyme functions, representing a significant advancement in formulating diets crucial for successful octopus farming that may help to fully understand its physiology.

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder affecting 1:3500 male births and is associated with myofiber degeneration, regeneration, and inflammation. Glucocorticoid treatments have been the standard of care due to immunomodulatory/immunosuppressive properties but novel genetic approaches, including exon skipping and gene replacement therapy, are currently being developed. The identification of additional biomarkers to assess DMD-related inflammatory responses and the potential efficacy of these therapeutic approaches are thus of critical importance. The current study uses RNA sequencing of skeletal muscle from two mdx mouse models to identify high mobility group box 1 (HMGB1) as a candidate biomarker potentially contributing to DMD-related inflammation. HMGB1 protein content was increased in a human iPSC-derived skeletal myocyte model of DMD and microdystrophin treatment decreased HMGB1 back to control levels. In vivo, HMGB1 protein levels were increased in vehicle treated B10-mdx skeletal muscle compared to B10-WT and significantly decreased in B10-mdx animals treated with adeno-associated virus (AAV)-microdystrophin. However, HMGB1 protein levels were not increased in D2-mdx skeletal muscle compared to D2-WT, demonstrating a strain-specific difference in DMD-related immunopathology.

Time-lapse microscopy has emerged as a crucial tool in cell biology, facilitating a deeper understanding of dynamic cellular processes. While existing tracking tools have proven effective in detecting and monitoring objects over time, the quantification of signals within these tracked objects often faces implementation constraints. In the context of infectious diseases, the quantification of signals at localized compartments within the cell and around intracellular pathogens can provide even deeper insight into the interactions between the pathogen and host cell organelles. Existing quantitative analysis at a single-phagosome level remains limited and dependent on manual tracking methods. We developed a near-fully automated workflow that performs with limited bias, high-throughput cell segmentation and quantitative tracking of both single cell and single bacterium/phagosome within multi-channel, z-stack, time-lapse confocal microscopy videos. We took advantage of the PyImageJ library to bring Fiji functionality into a Python environment and combined deep-learning-based segmentation from Cellpose with tracking algorithms from Trackmate. The 'da_tracker' workflow provides a versatile toolkit of functions for measuring relevant signal parameters at the single-cell level (such as velocity or bacterial burden) and at the single-phagosome level (i.e. assessment of phagosome maturation over time). Its capabilities in both single-cell and single-phagosome quantification, its flexibility and open-source nature should assist studies that aim to decipher for example the pathogenicity of bacteria and the mechanism of virulence factors that could pave the way for the development of innovative therapeutic approaches.

The cephalopod eye lens is unique because it has evolved as a compound structure with two physiologically distinct segments. However, the detailed ultrastructure of this lens and precise optical role of each segment are far from clear. To help elucidate structure-function relationships in the cephalopod lens, we conducted multiple structural investigations on squid. Synchrotron x-ray scattering and transmission electron microscopy disclose that an extensive network of structural features that resemble cell membrane complexes form a substantial component of both anterior and posterior lens segments. Optically, the segments are distinct, however, and Talbot interferometry indicates that the posterior segment possesses a noticeably higher refractive index gradient. We propose that the hitherto unrecognised network of membrane structures in the cephalopod lens has evolved to act as an essential conduit for the internal passage of ions and other metabolic agents through what is otherwise a highly dense structure owing to a very high protein concentration.

Alterations to intra- and inter-limb coordination with improved maximal velocity performance remain largely unexplored. This study quantified within-day variability in lower-limb segmental coordination profiles during maximal velocity sprinting and investigated the modifications to coordination strategies in 15 recreationally active males following a 6-week period comprised of a multimodal training programme [intervention group (INT); n=7] or continued participation in sports (control group; n=8). The INT demonstrated a large decrease (effect size=-1.54) in within-day coordination profile variability, suggesting potential skill development. Thigh-thigh coordination modifications for the INT were characterised by an earlier onset of trail thigh reversal in early swing (26 versus 28% stride) and lead thigh reversal in late swing (76 versus 79% stride), rather than increases in overall time spent in anti-phase. Moreover, an increase in backward rotation of thigh relative to shank (effect size, 95% CIs: 0.75, 0.17 to 1.33) and shank relative to foot (0.76, -0.17 to 1.68) during late swing likely facilitated more aggressive acceleration of the limb, contributing to reduced touchdown distance and more favourable lower-limb configuration at initial ground contact. These novel findings provide empirical support for the role of longitudinal coordination modifications in improving maximal velocity performance.

North American bison (Bovidae: Bison bison) incur blunt impacts to the interparietal and frontal bones when they engage in head-to-head fights. To investigate the impact mitigation of these bones, a finite element analysis (FEA) of the skull under loading conditions was performed. Based on anatomical and histological studies, the interparietal and frontal bones are both comprised of a combination of haversian and plexiform bone and are both underlain by bony septa. Additionally, the interparietal bone is thicker than the frontal bone. Data regarding the mechanical properties of bison bone are scarce, but the results of a phylogenetic analysis infer that the material properties of the closely related domestic cow bone are a suitable proxy for use in the FEA. Results of the FEA suggest that the thickness of the interparietal bone in conjunction with the bony septa may prevent fracture stresses by helping to absorb and disperse the blunt impact energy throughout the skull. Monotonic stress levels of 294 MPa, which are below the compressive strength of bone were exhibited in the simulated bison head impacts indicating no fracture of the bones.

Interspecific hybridisation increases genetic diversity and has played a significant role in the evolution of corals in the genus Acropora. In vitro fertilisation can be used to increase the frequency of hybridisation among corals, potentially enhancing their ability to adapt to climate change. Here, we assessed the field performance of hybrids derived from the highly cross-fertile coral species Acropora sarmentosa and Acropora florida from the Great Barrier Reef. Following outplanting to an inshore reef environment, the 10-month survivorship of the hybrid offspring groups was intermediate between that of the purebred groups, although not all pairwise comparisons were statistically significant. The A. florida purebreds, which had the lowest survivorship, were significantly larger at 10 months post-deployment compared to the other three groups. The four offspring groups harboured the same intracellular photosymbiont communities (Symbiodiniaceae), indicating that observed performance differences were due to the coral host and not photosymbiont communities. The limited differences in the performance of the groups and the lack of outbreeding depression of the F1 hybrids in the field suggest that interspecific hybridisation may be a useful method to boost the genetic diversity, and as such increase the adaptive capacity, of coral stock for restoration of degraded and potentially genetically eroded populations.