Since the initial identification of oncogenic Wnt in mice and Drosophila, the Wnt signaling pathway has been subjected to thorough and extensive investigation. Persistent activation of Wnt signaling exerts diverse cancer characteristics, encompassing tumor initiation, tumor growth, cell senescence, cell death, differentiation, and metastasis. Here we review the principal signaling mechanisms and the regulatory influence of pathway-intrinsic and extrinsic kinases on cancer progression. Additionally, we underscore the divergences and intricate interplays of the canonical and non-canonical Wnt signaling pathways and their critical influence in cancer pathophysiology, exhibiting both growth-promoting and growth-suppressing roles across diverse cancer types.

The Morada Nova sheep breed is essential for the economy of the semi-arid region of Northeast Brazil, standing out for its adaptability, resistance to parasites and reproductive ability. However, the white variant is endangered, highlighting the importance of studies on its productivity to support conservation efforts. This study focuses on the growth curve of the Morada Nova sheep breed, using nonlinear models and analyzing flock profiles. Total of 764 observations of 165 animals from four farms in Ceará and Rio Grande do Norte, Brazil, were analyzed. Canonical discriminant analysis (CDA) was used for the exploratory analysis and four nonlinear models were used to study the growth curve. Weight from birth to 270 days of age, absolute growth rate (AGR), and the impact of sex on growth curves were assessed. Sex and farm are significant discriminating variables (P < 0.05) for the studied effects (weight and age). Weight was the primary phenotypic biomarker that discriminated between the two indicators, while age was a discriminating indicator only for the core effect. The Gompertz model was the most efficient, presenting the lowest residuals and greatest convergence. The study reveals new information about the growth of Morada Nova sheep, the white variety, including weight differences between the sexes at all analyzed ages and an inflection point before 90 days of age. These discoveries contribute to the understanding of the breed\'s growth and help in the formulation of conservation strategies.

OBJECTIVE: The aim of this study was to understand the temporal and spatial distribution of canonical endochondral ossification (CEO) and non-canonical endochondral ossification (NCEO) of the normal growing rat condyle, and to evaluate their histomorphological changes following the simultaneous hypotrophy of the unilateral masticatory closing muscles with botulinum toxin (BTX).
METHODS: 46 rats at postnatal 4 weeks were used for the experiment and euthanized at postnatal 4, 8, and 16 weeks. The right masticatory muscles of rats in experimental group were injected with BTX, the left being injected with saline as a control. The samples were evaluated using 3D morphometric, histological, and immunohistochemical analysis with three-dimensional regional mapping of endochondral ossifications.
RESULTS: The results showed that condylar endochondral ossification changed from CEO to NCEO at the main articulating surface during the experimental period and that the BTX-treated condyle presented a retroclined smaller condyle with an anteriorly-shifted narrower articulating surface. This articulating region showed a thinner layer of the endochondral cells, and a compact distribution of flattened cells. These were related to the load concentration, decreased cellular proliferation with thin cellular layers, reduced extracellular matrix, increased cellular differentiation toward the osteoblastic bone formation, and accelerated transition of the ossification types from CEO to NCEO.
CONCLUSIONS: The results suggest that endochondral ossification under loading tended to show more NCEO, and that masticatory muscular hypofunction by BTX had deleterious effects on endochondral bone formation and changed the condylar growth vector, resulting in a retroclined, smaller, asymmetrical, and deformed condyle with thin cartilage.

In all cell types, small EVs, very abundant extracellular vesicles, are generated and accumulated within MVB endocytic cisternae. Upon MVB fusion and exocytosis with the plasma membrane, the EVs are released to the extracellular space. In the central nervous system, the release of neuronal EVs was believed to occur only from the surface of the body and dendrites. About 15 years ago, MVB cisternae and EVs were shown to exist and function at synaptic boutons, the terminals\' pre- and post-synaptic structures essential for canonical neurotransmitter release. Recent studies have revealed that synaptic EVs are peculiar in many respects and heterogeneous with respect to other neuronal EVs. The distribution of synaptic EVs and the effect of their specific molecules are found at critical sites of their distribution. The role of synaptic EVs could consist of the modulation of canonical neurotransmitter release or a distinct, non-canonical form of neurotransmission. Additional roles of synaptic EVs are still not completely known. In the future, additional investigations will clarify the role of synaptic EVs in pathology, concerning, for example, circuits, trans-synaptic transmission, diagnosis and the therapy of diseases.

Biscuit bran (BB) is a co-product with worldwide distribution, with Brazil as the second largest cookie producer in the world with 1,157,051 tons. We evaluate the impact of completely replacing corn with BB on the characteristics and morphometry of carcass of purebred and crossbred Morada Nova lambs using machine learning techniques as an auxiliary method. Twenty male lambs from two genetic groups (GG) were used: purebred red-coated Morada Nova (MNR) and crossbred MNR × white-coated Morada Nova (MNF1). Supervised and unsupervised machine learning techniques were used. No interaction (P > 0.05) was observed between diets (D) and genetic groups (GG) and no simple isolated effect was observed for carcass characteristics, qualitative-quantitative typification of the Longissimus dorsi muscle, weight of non-carcass components, weight and yield of commercial cuts and carcass morphometric measurements. The formation of two horizontal clusters was verified: (i) crossed lambs with corn and BB and (ii) purebred lambs fed corn and BB. Vertically, three clusters were formed based on carcass and meat characteristics of native lambs: (i) thermal insulation, body capacity, true yield, and commercial cuts; (ii) choice, performance, physical carcass traits, and palatability; and (iii) yield cuts and non-carcass components. The heatmap also allowed us to observe that pure MN lambs had a greater body capacity when fed BB, while those fed corn showed superiority in commercial cuts, true yields, and non-carcass components. Crossbred lambs, regardless of diet, showed a greater association of physical characteristics of the carcass, performance, palatability, and less noble cuts. Crossbred lambs, regardless of diet, showed a greater association of physical characteristics of the carcass, performance, palatability, and less noble cuts. BB can be considered an alternative energy source in total replacement of corn. Integrating of machine learning techniques is a useful statistical tool for studies with large numbers of variables, especially when it comes to analyzing complex data with multiple effects in the search for data patterns and insights in decision-making on the farm.

Inflammasomes are complex platforms for the cleavage and release of inactivated IL-1β and IL-18 cytokines that trigger inflammatory responses against damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). Gut microbiota plays a pivotal role in maintaining gut homeostasis. Inflammasome activation needs to be tightly regulated to limit aberrant activation and bystander damage to the host cells. Several types of inflammasomes, including Node-like receptor protein family (e.g., NLRP1, NLRP3, NLRP6, NLRP12, NLRC4), PYHIN family, and pyrin inflammasomes, interact with gut microbiota to maintain gut homeostasis. This review discusses the current understanding of how inflammasomes and microbiota interact, and how this interaction impacts human health. Additionally, we introduce novel biologics and antagonists, such as inhibitors of IL-1β and inflammasomes, as therapeutic strategies for treating gastrointestinal disorders when inflammasomes are dysregulated or the composition of gut microbiota changes.

With self-renewal and pluripotency features, embryonic stem cells (ESCs) provide an invaluable tool to investigate early cell fate decisions. Pluripotency exit and lineage commitment depend on precise regulation of gene expression that requires coordination between transcription (TF) and chromatin factors in response to various signaling pathways. SET domain-containing 3 (SETD3) is a methyltransferase that can modify histones in the nucleus and actin in the cytoplasm. Through an shRNA screen, we previously identified SETD3 as an important factor in the meso/endodermal lineage commitment of mouse ESCs (mESC). In this study, we identified SETD3-dependent transcriptomic changes during endoderm differentiation of mESCs using time-course RNA-seq analysis. We found that SETD3 is involved in the timely activation of the endoderm-related gene network. The canonical Wnt signaling pathway was one of the markedly altered signaling pathways in the absence of SETD3. The assessment of Wnt transcriptional activity revealed a significant reduction in Setd3-deleted (setd3∆) mESCs coincident with a decrease in the nuclear pool of the key TF β-catenin level, though no change was observed in its mRNA or total protein level. Furthermore, a proximity ligation assay (PLA) found an interaction between SETD3 and β-catenin. We were able to rescue the differentiation defect by stably re-expressing SETD3 or activating the canonical Wnt signaling pathway by changing mESC culture conditions. Our results suggest that alterations in the canonical Wnt pathway activity and subcellular localization of β-catenin might contribute to the endoderm differentiation defect of setd3∆ mESCs.

Over 35 years ago the cell biology community was introduced to connexins as the subunit employed to assemble semicrystalline clusters of intercellular channels that had been well described morphologically as gap junctions. The decade that followed would see knowledge of the unexpectedly large 21-member human connexin family grow to reflect unique and overlapping expression patterns in all organ systems. While connexin biology initially focused on their role in constructing highly regulated intercellular channels, this was destined to change as discoveries revealed that connexin hemichannels at the cell surface had novel roles in many cell types, especially when considering connexin pathologies. Acceptance of connexins as having bifunctional channel properties was initially met with some resistance, which has given way in recent years to the premise that connexins have multifunctional properties. Depending on the connexin isoform and cell of origin, connexins have wide-ranging half-lives that vary from a couple of hours to the life expectancy of the cell. Diversity in connexin channel characteristics and molecular properties were further revealed by X-ray crystallography and single-particle cryo-EM. New avenues have seen connexins or connexin fragments playing roles in cell adhesion, tunneling nanotubes, extracellular vesicles, mitochondrial membranes, transcription regulation, and in other emerging cellular functions. These discoveries were largely linked to Cx43, which is prominent in most human organs. Here, we will review the evolution of knowledge on connexin expression in human adults and more recent evidence linking connexins to a highly diverse array of cellular functions.

Programmed cell death pathways play important roles in a wide variety of physiological processes. Although it has similarities with apoptosis pyroptosis is a different type of programmed cell death. Pyroptosis can be triggered by different molecules originating from the cells or their environment. Once a pyroptotic pathway is started, it is followed by different molecular steps, and, it ends with the disruption of cell membrane integrity and the onset of inflammatory processes. In addition to the role of pyroptosis in the host\'s innate immunity against pathogens, uncontrolled pyroptosis can lead to increased inflammation and lead various diseases. The contradictory role of pyroptosis-related molecular changes in the pathogenesis of cancer has attracted attention lately. Excessive or decreased expression of molecules involved in pyroptotic pathways is associated with various cancers. There are ongoing studies on the use of different treatment methods for cancer in combination with new therapies targeting pyroptosis. The potential beneficial effects or side-effect profiles of these protocols targeting pyroptosis still need to be investigated. This will provide us with more efficient and safer options to treat cancer. This review aims to overview the main pathways and mechanisms of pyroptosis and to discuss its role in cancer.

In Mycobacterium tuberculosis, bedaquiline and clofazimine resistance occurs primarily through Rv0678 variants, a gene encoding a repressor protein that regulates mmpS5/mmpL5 efflux pump gene expression. Despite the shared effect of both drugs on efflux, little else is known about other pathways affected. We hypothesized that in vitro generation of bedaquiline- or clofazimine-resistant mutants could provide insight into additional mechanisms of action. We performed whole-genome sequencing and determined phenotypic MICs for both drugs on progenitor and mutant progenies. Mutants were induced through serial passage on increasing concentrations of bedaquiline or clofazimine. Rv0678 variants were identified in both clofazimine- and bedaquiline-resistant mutants, with concurrent atpE SNPs occurring in the latter. Of concern was the acquisition of variants in the F420 biosynthesis pathway in clofazimine-resistant mutants obtained from either a fully susceptible (fbiD: del555GCT) or rifampicin mono-resistant (fbiA: 283delTG and T862C) progenitor. The acquisition of these variants possibly implicates a shared pathway between clofazimine and nitroimidazoles. Pathways associated with drug tolerance and persistence, F420 biosynthesis, glycerol uptake and metabolism, efflux, and NADH homeostasis appear to be affected following exposure to these drugs. Shared genes affected by both drugs include Rv0678, glpK, nuoG, and uvrD1. Genes with variants in the bedaquiline resistant mutants included atpE, fadE28, truA, mmpL5, glnH, and pks8, while clofazimine-resistant mutants displayed ppsD, fbiA, fbiD, mutT3, fadE18, Rv0988, and Rv2082 variants. These results show the importance of epistatic mechanisms as a means of responding to drug pressure and highlight the complexity of resistance acquisition in M. tuberculosis.