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Feathers, the primary skin appendage covering the avian body, undergo dynamic phenotypic changes throughout a bird’s life. Males and females of the same species can exhibit sexually dichromatic plumage colors which play a critical role in mating choice, survival, and ecological interactions. In this study, we investigate the molecular mechanisms underlying the changes of color that occur during the transition from juvenile to adult feathers, known as the secondary transition. We focus on sexual dichromatism of craniofacial plumage and use the male cheek domain of the zebra finch ( Taeniopygia guttata ) as the major model. The transcriptome of the cheek and scalp (crown) domains in males and females of wild-type and genetic color variants were compared. We found that (1) Craniofacial color patterning operates through two regulatory layers. The first layer involves transcription factor (TF) genes that define the cheek domain such as PITX1, PAX1, PAX6. The second layer comprises pigment-related genes responsible for specific colors, including male-biased TFs (SOX10 and DMRT1) and transporters associated with red pigment synthesis. (2) Surprisingly, ASIP , which controls pheomelanin production in other species, was expressed in both male (red) and female (gray) cheeks. Instead, PAX1 in cheek dermal fibroblasts may serve as an upstream regulator, potentially triggering the male-biased color pattern through PAX6 and SOX10. PAX6 and SOX10 in melanocytes potentially enhance the expression of GPR143 , SLC45A2 , and TMEM163 , driving increased pheomelanin production in males. (3) Sexual dichromatism is associated with sex-linked genes on the Z chromosome, notably SLC45A2 . In addition, motif analysis comparing the binding strength between regional transcription factors and melanogenesis genes suggests that craniofacial pigmentation may have evolved convergently in passerine birds. These findings provide novel insights into the molecular control of color patterning and lay the groundwork for further studies on avian sexual dichromatism and secondary feather transition.

Developmental processes extend beyond embryogenesis to support lifelong tissue adaptations. Avian feather follicles, with their resident stem cells and capacity for cyclic regeneration, provide a dynamic model for postnatal tissue remodeling. Here, we propose the Mandarin duck ( Aix galericulata ) as an ideal model to study lifelong developmental modulation, focusing on the sexually dimorphic “sail feather”—a secondary flight feather in males that undergoes seasonal transformation into a strikingly asymmetric, ornamented phenotype during the breeding season. We identified asymmetric morphogen expression in regenerating male sail feathers and used transcriptome and H3K27ac ChIP-seq to uncover male and female signaling pathways and regulatory elements. Comparative epigenomic profiling reveals enriched estrogen receptor binding motifs in females. Hormone profiling shows seasonal variation, with a marked rise in female estrogen levels preceding the mating season. These results imply Mandarin duck sail feathers integrate local morphogenetic programs, epigenetic regulation, and systemic hormonal cues to orchestrate sexually dimorphic and seasonally dynamic feather morphogenesis. This work establishes a framework for further mechanistic study of the interplay between regeneration, regional identity, and hormonal plasticity in a vertebrate integumentary system.

Background Meniscus diseases present certain therapeutic limitations. Although meniscectomy is the primary treatment option for meniscus injury (MI), this approach may accelerate the development of osteoarthritis and other degenerative joint diseases, and its therapeutic efficacy remains controversial. While human mesenchymal stem cells (MSCs) have emerged as a promising treatment option for MI, particularly in promoting cell proliferation and preventing apoptosis, their effect on activating endogenous meniscus progenitor cells (MPCs) to ameliorate MI and the underlying mechanisms remain unclear. Methods The secretome was collected from human placenta-derived MSCs (pcMSCs). A cellular model of MI was established by challenging mouse MPCs with H 2 O 2 . Male C57BL/6 mouse model of MI was established by mechanically destabilizing the medial meniscus (DMM). Protein expression was analyzed through Western blotting, flow cytometry, and immunohistochemistry staining. After secretome administration, behavioral activity was assessed through gait analysis and rotarod tests. Key secretome factors were identified through cytokine arrays and microRNA (miRNA) analysis. Results The pcMSC secretome significantly mitigated MI in both cellular and mouse models, as indicated by gait analysis ( P  < 0.05), rotarod tests ( P  < 0.01), histological analysis (safranin-O staining, P  < 0.001), and immunohistochemical staining for apoptosis marker (Caspase-3) and MPC proliferation markers (Gli-1, Sca-1, and Ki67). Cytokine arrays revealed several factors associated with immunomodulation (MCP1 and MCP3), regeneration and angiogenesis (IGF-1, ANG, and VEGFA), osteogenesis (OPG and OPN), and extracellular matrix preservation (TIMP1 and TIMP2). Furthermore, exosomal miRNA analysis revealed target genes involved in endogenous stem cell activation ( SUFU and RUNX2 ), apoptosis regulation ( Caspase-3 ), anti-inflammatory responses ( IL-1β , IL-6 , and PTEN ), ECM formation ( TRAF6 and MMPs ), anti-cartilage matrix degradation ( mTOR , AKT2 , AKT3 , and COL10A1 ), and cell migration ( ADAM family ). Conclusions To the best of our knowledge, this is the first study demonstrating that the human pcMSC secretome promotes meniscus regeneration through activating endogenous meniscus progenitor cells both in vivo and in vitro. Our findings suggest that these regenerative effects are mediated by growth factors and exosomal miRNAs in the pcMSC secretome. The potential exosomal miRNAs effectively modulated ECM formation, anti-apoptosis, anti-inflammation, and anti-cartilage matrix degradation to mitigate MPCs injury. Overall, this study provides valuable insights into potential stem cell-derived secretome cell-free therapies for patients with exercise-induced meniscus injuries.

The role of a YAP-IGF-1R signaling loop in HCC resistance to sorafenib remains unknown. Method: Sorafenib-resistant cells were generated by treating naïve cells (HepG2215 and Hep3B) with sorafenib. Different cancer cell lines from databases were analyzed through the ONCOMINE web server. BIOSTORM–LIHC patient tissues (46 nonresponders and 21 responders to sorafenib) were used to compare YAP mRNA levels. The HepG2215_R-derived xenograft in SCID mice was used as an in vivo model. HCC tissues from a patient with sorafenib failure were used to examine differences in YAP and IGF-R signaling. Results: Positive associations exist among the levels of YAP, IGF-1R, and EMT markers in HCC tissues and the levels of these proteins increased with sorafenib failure, with a trend of tumor-margin distribution in vivo. Blocking YAP downregulated IGF-1R signaling-related proteins, while IGF-1/2 treatment enhanced the nuclear translocation of YAP in HCC cells through PI3K-mTOR regulation. The combination of YAP-specific inhibitor verteporfin (VP) and sorafenib effectively decreased cell viability in a synergistic manner, evidenced by the combination index (CI). Conclusion: A YAP-IGF-1R signaling loop may play a role in HCC sorafenib resistance and could provide novel potential targets for combination therapy with sorafenib to overcome drug resistance in HCC.

The epidermal differentiation complex (EDC) encodes a group of unique proteins expressed in late epidermal differentiation. The EDC gave integuments new physicochemical properties and is critical in evolution. Recently, we showed β-keratins, members of the EDC, undergo gene cluster switching with overexpression of SATB2 (Special AT-rich binding protein-2), considered a chromatin regulator. We wondered whether this unique regulatory mechanism is specific to β-keratins or may be derived from and common to EDC members. Here we explore (1) the systematic expression patterns of non-β-keratin EDC genes and their preferential expression in different skin appendages during development, (2) whether the expression of non-β-keratin EDC sub-clusters are also regulated in clusters by SATB2. We analyzed bulk RNA-seq and ChIP-seq data and also evaluated the disrupted expression patterns caused by overexpressing SATB2. The results show that the expression of whole EDDA and EDQM sub-clusters are possibly mediated by enhancers in E14-feathers. Overexpressing SATB2 down-regulates the enriched EDCRP sub-cluster in feathers and the EDCH sub-cluster in beaks. These results reveal the potential of complex epigenetic regulation activities within the avian EDC, implying transcriptional regulation of EDC members acting at the gene and/or gene cluster level in a temporal and skin regional-specific fashion, which may contribute to the evolution of diverse avian integuments.

Aphids are hemimetabolous insects that undergo incomplete metamorphosis without pupation. The annual life cycle of most aphids includes both an asexual (viviparous) and a sexual (oviparous) phase. Sexual reproduction only occurs once per year and is followed by many generations of asexual reproduction, during which aphids propagate exponentially with telescopic development. Here, we discuss the potential links between viviparous embryogenesis and derived developmental features in the pea aphid Acyrthosiphon pisum, particularly focusing on germline specification and axis determination, both of which are key events of early development in insects. We also discuss potential evolutionary paths through which both viviparous and oviparous females might have come to utilize maternal germ plasm to drive germline specification. This developmental strategy, as defined by germline markers, has not been reported in other hemimetabolous insects. In viviparous females, furthermore, we discuss whether molecules that in other insects characterize germ plasm, like Vasa, also participate in posterior determination and how the anterior localization of the hunchback orthologue Ap-hb establishes the anterior-posterior axis. We propose that the linked chain of developing oocytes and embryos within each ovariole and the special morphology of early embryos might have driven the formation of evolutionary novelties in germline specification and axis determination in the viviparous aphids. Moreover, based upon the finding that the endosymbiont Buchnera aphidicola is closely associated with germ cells throughout embryogenesis, we propose presumptive roles for B. aphidicola in aphid development, discussing how it might regulate germline migration in both reproductive modes of pea aphids. In summary, we expect that this review will shed light on viviparous as well as oviparous development in aphids.

Formation of the germ plasm drives germline specification in Drosophila and some other insects such as aphids. Identification of the DEAD-box protein Vasa (Vas) as a conserved germline marker in flies and aphids suggests that they share common components for assembling the germ plasm. However, to which extent the assembly order is conserved and the correlation between functions and sequences of Vas remain unclear. Ectopic expression of the pea aphid Vas (ApVas1) in Drosophila did not drive its localisation to the germ plasm, but ApVas1 with a replaced C-terminal domain (HELICc) of Drosophila Vas (DmVas) became germ-plasm restricted. We found that HELICc itself, through the interaction with Oskar (Osk), was sufficient for germ-plasm localisation. Similarly, HELICc of the grasshopper Vas could be recruited to the germ plasm in Drosophila . Nonetheless, germ-plasm localisation was not seen in the Drosophila oocytes expressing HELICcs of Vas orthologues from aphids, crickets and mice. We further identified that glutamine (Gln) 527 within HELICc of DmVas was critical for localisation and its corresponding residue could also be detected in grasshopper Vas yet missing in the other three species. This suggests that Gln527 is a direct target of Osk or critical to the maintenance of HELICc conformation.

In the parthenogenetic and viviparous pea aphid Acyrthosiphon pisum, germline specification depends on the germ plasm localized to the posterior region of the egg chamber before the formation of the blastoderm. During blastulation, germline segregation occurs at the egg posterior, and in early gastrulation germ cells are pushed inward by the invaginating germ band. Previous studies suggest that germ cells remain dorsal in the embryo in subsequent developmental stages. In fact, though, it is not known whether germ cells remain in place or migrate dynamically during katatrepsis and germ-band retraction. We cloned Apvasa, a pea aphid homologue of Drosophila vasa, and used it as a germline marker to monitor the migration of germ cells. Apvasa messenger RNA (mRNA) was first restricted to morphologically identifiable germ cells after blastoderm formation but that expression soon faded. Apvasa transcripts were again identified in germ cells from the stage when the endosymbiotic bacteria invaded the embryo, and after that, Apvasa mRNA was present in germ cells throughout all developmental stages. At the beginning of katatrepsis, germ cells were detected at the anteriormost region of the egg chamber as they were migrating into the body cavity. During the early period of germ-band retraction, germ cells were separated into several groups surrounded by a layer of somatic cells devoid of Apvasa staining, suggesting that the coalescence between migrating germ cells and the somatic gonadal mesoderm occurs between late katatrepsis and early germ-band retraction.