Specific Role Research Articles

Cloning, identification, and functional analysis of foxl2 gene and its expression after 17β‐estradiol (E2) treatment in Dabry’s sturgeon, Acipenser dabryanus

The study focuses on the critically endangered Dabry’s sturgeon (Acipenser dabryanus), a species on the brink of extinction in the wild. This research investigates the role of the Forkhead box protein L2 (foxl2) in the gonadal development and differentiation of this species. The foxl2 gene, known for its role in various physiological processes, including sexual maturation, is hypothesized to play a significant role in the sex differentiation of Dabry’s sturgeon. This study cloned the full-length cds sequence of the foxl2 gene and analyzed its expression across various tissues, focusing on its response to estradiol treatment. Our findings indicate that foxl2 is predominantly expressed in ovaries and shows a dose-dependent response to estradiol, suggesting its potential role in ovarian differentiation. This research underscores the importance of foxl2 in understanding reproductive biology and offers a foundation for future conservation strategies.

Regulation of TGF-β1-induced fibroblast differentiation of human periodontal ligament stem cells through the mutually antagonistic action of ectonucleotide pyrophosphatase/phosphodiesterase 1 and 2.

Human periodontal ligament stem cells (hPDLSCs) differentiate into periodontal ligament (PDL) fibroblasts, osteoblasts, and cementoblasts. To identify inducers of PDL fibroblastic differentiation, monoclonal antibody series were developed a series of against membrane/extracellular matrix (ECM) molecules through decoy immunization. The anti-PDL13 antibody targets ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), renowned for regulating skeletal and soft tissue mineralization. ENPP1 accumulates in the periodontal ligament region of tooth roots, and specifically localizes to the cell boundaries and elongated processes of the fibroblastic cells. As ENPP1 expression increases during fibroblastic differentiation, mineralization induced by tissue-nonspecific alkaline phosphatase (TNAP), a pyrophosphate-degrading enzyme, is completely inhibited. This is consistent with ENPP1 and TNAP acting in opposition, and TGF-β1-induced ENPP1 expression creates an essential environment for PDL fibroblast differentiation. Representative fibroblastic differentiation markers decrease with endogenous ENPP1 inhibition by siRNA and antibody blocking. ENPP2 generates lipid signaling molecules. In contrast to ENPP1, ENPP2 disappears in TGF-β1-induced PDL fibroblasts. Ectopic expression of ENPP2 hinders TGF-β1-induced PDL fibroblastic differentiation. Suppression of ENPP1 and ENPP2 leads to severe defects in undifferentiated and differentiated cells, demonstrating that these two factors play opposing roles in soft and hard tissue differentiation but can complement each other for cell survival. In conclusion, increased ENPP1 is crucial for TGF-β1-induced PDL differentiation, while ENPP2 and TNAP can inhibit ENPP1. ENPP1 and ENPP2 exhibit complementary functions in the cell survival.

Glycoside hydrolases reveals their differential role in response to drought and salt stress in potato (Solanum tuberosum)

Glycoside hydrolases (GHs) are important in metabolic processes involving diverse carbohydrate-based substances found inside plant tissues. Potatoes (Solanum tuberosum) are rich in starchy carbohydrates, suggesting the role of GHs in their metabolic pathways. In this study, we examine the GH superfamily in potato where 366 potential GHs were identified using a similarity search method. Genes were subjected to further characterisation to gain insights into their structural composition, functional properties and distribution patterns across tissue types. Several in silico methodologies were also employed to investigate the physicochemical features, conserved motifs, chromosomal mapping, duplication events, syntenic links with tomato (Solanum lycopersicum), subcellular localisations, secondary structures and phylogenetic relationships. Cis-elements in StGHs revealed that the promoters of StGHs contain cis-elements that are responsive to phytohormones that are involved in plant growth and development, and are associated with stress responses. RNA-seq data identified significant changes in expression levels of GH16, GH17, GH18, GH19 and GH28 members under stress conditions. Expression patterns of several GHs were confirmed using real time quantitative PCR in response to stress. StGH16.24 expression increased after 3 days of drought stress, whereas StGH16.30 continuously increased under salt stress. Potential interactions between potato miRNAs and StGH revealed 393 and 627 interactions under drought and salt stress, respectively. Our findings offer insights into specific functions of GHs in diverse developmental stages and stress-related challenges in potato and other plants.

Evaluating a novel method for vitamin A analysis in an observational study of the UAE's obese population

Vitamin A plays a critical role in various biological functions, including vision, cellular differentiation, and immune regulation. However, accurately assessing its status, particularly in obese individuals, presents challenges due to potential alterations in metabolism and distribution. This study utilized Liquid Chromatography–Tandem Mass Spectrometry (LC–MS/MS) methodology to precisely measure serum vitamin A concentrations in population of UAE. The methodology's reliability and precision, as demonstrated through validation procedures, underscore its potential utility in clinical settings. Employing the Multiple Reaction Monitoring mode of positive ion electrospray ionization, the LC–MS/MS system achieves a limit of detection (LOD) of 0.48 ng/mL in serum, while adhering to FDA-US regulations for accuracy and compliance. A key aspect of this study was the application of LC–MS/MS to assess vitamin A status in an obese population within UAE. By employing a diverse cohort of 452 Emirati participants, including 277 individuals from a randomized controlled trial who were assessed at baseline and at 6th month, and 175 healthy individuals aged 18–82 assessed at baseline, this study explores the relationship between obesity and vitamin A levels, shedding light on potential implications for health and well-being. It was an observational study based on a new vitamin A method and participants were asked to eat vitamin A rich foods. The robust performance of the LC–MS/MS methodology positions it as a valuable tool for clinical research. By accurately quantifying vitamin A levels in human serum, this methodology opens avenues for advancing our understanding of vitamin A physiology and its implications for health, particularly in obese populations. In summary, this LC–MS/MS methodology presents a potent tool for clinical studies, providing reliable, specific, and robust detection of vitamin A in human serum, thus, opening a new frontier for advancing our understanding of vitamin A related physiology and health in the obese population.

Differential roles for the oxygen sensing enzymes PHD1 and PHD3 in the regulation of neutrophil metabolism and function.

Neutrophils are essential in the early innate immune response to pathogens. Harnessing their antimicrobial powers, without driving excessive and damaging inflammatory responses, represents an attractive therapeutic possibility. The neutrophil population is increasingly recognised to be more diverse and malleable than was previously appreciated. Hypoxic signalling pathways are known to regulate important neutrophil behaviours and, as such, are potential therapeutic targets for regulating neutrophil antimicrobial and inflammatory responses. We used a combination of in vivo and ex vivo models, utilising neutrophil and myeloid specific PHD1 or PHD3 deficient mouse lines to investigate the roles of oxygen sensing prolyl hydroxylase enzymes in the regulation of neutrophilic inflammation and immunity. Mass spectrometry and Seahorse metabolic flux assays were used to analyse the role of metabolic shifts in driving the downstream phenotypes. We found that PHD1 deficiency drives alterations in neutrophil metabolism and recruitment, in an oxygen dependent fashion. Despite this, PHD1 deficiency did not significantly alter ex vivo neutrophil phenotypes or in vivo outcomes in mouse models of inflammation. Conversely, PHD3 deficiency was found to enhance neutrophil antibacterial properties without excessive inflammatory responses. This was not linked to changes in the abundance of core metabolites but was associated with increased oxygen consumption and increased mitochondrial reactive oxygen species (mROS) production. PHD3 deficiency drives a favourable neutrophil phenotype in infection and, as such, is an important potential therapeutic target.

CircHIPK3 regulates cementoblast differentiation via the miR-10b-5p/DOHH/NF-κB axis

BackgroundIntact cementum is vital for tooth stability and health. Cementoblasts, which line the root surface, are responsible for cementum formation. Recent evidence suggests that circular RNAs (circRNAs) are involved in various cellular functions and may have clinical applications. Although circHIPK3 has been shown to participate in osteogenesis, its role in cementoblast differentiation and mineralization is not well understood. MethodsThe ring structure of circHIPK3 was confirmed using Sanger sequencing and an actinomycin D assay. Subcellular localization of circHIPK3 was assessed using a nucleus-cytoplasm separation assay. RT-qPCR was employed to analyze circHIPK3 expression during cementoblast differentiation and following TNF-α treatment. In vivo, periapical lesions were induced in mouse mandibular first molars to mimic an inflammatory environment, and circHIPK3 expression was evaluated. The interaction of the circHIPK3/miR-10b-5p/DOHH axis was explored through RNA pull-down assays, bioinformatics analysis, and dual-luciferase reporter assays. The effects on cementoblast differentiation and mineralization were assessed by measuring osteogenic markers, alkaline phosphatase (ALP) activity, ALP staining, and alizarin red S staining. ResultsCircHIPK3 was predominantly located in the cytoplasm of cementoblasts, and its expression was significantly upregulated during cementoblast differentiation. Knockdown of circHIPK3 inhibited cementoblast differentiation and mineralization, whereas its overexpression promoted these processes. Mechanistically, circHIPK3 upregulated DOHH expression by sponging miR-10b-5p, thereby enhancing cementoblast differentiation and mineralization. The NF-κB pathway was found to act downstream of the circHIPK3/miR-10b-5p/DOHH axis in these processes. Additionally, circHIPK3 expression was significantly downregulated in inflammatory environments both in vitro and in vivo. Forced overexpression of circHIPK3 mitigated the inhibitory effects of TNF-α on cementoblast differentiation and mineralization. ConclusionCircHIPK3 acts as a positive regulator of cementoblast differentiation and mineralization through the miR-10b-5p/DOHH/NF-κB axis, playing a crucial role in both normal and pathological cementogenesis.

GTPBP8 mitigates nonalcoholic steatohepatitis (NASH) by depressing hepatic oxidative stress and mitochondrial dysfunction via PGC-1α signaling

Nonalcoholic steatohepatitis (NASH) is emerging as a major cause of liver transplantation and hepatocellular carcinoma (HCC). Regrettably, its pathological mechanisms are still not fully comprehended. GTP-binding protein 8 (GTPBP8), belonging to the GTP-binding protein superfamily, assumes a crucial role in RNA metabolism, cell proliferation, differentiation, and signal transduction. Its aberrant expression is associated with oxidative stress and mitochondrial dysfunctions. Nevertheless, its specific functions and mechanisms of action, particularly in NASH, remain elusive. In our current study, we initially discovered that human hepatocytes L02 displayed evident mitochondrial respiratory anomaly, mitochondrial damage, and dysfunction upon treatment with palmitic acids and oleic acids (PO), accompanied by significantly reduced GTPBP8 expression levels through RNA-Seq, RT-qPCR, western blotting, and immunofluorescence assays. We then demonstrated that GTPBP8 overexpression mediated by adenovirus vector (Ad-GTPBP8) markedly attenuate lipid accumulation, inflammatory response, and mitochondrial impair and dysfunction in hepatocytes stimulated by PO. Conversely, adenovirus vector-mediated GTPBP8 knockdown (Ad-shGTPBP8) significantly accelerated lipid deposition, inflammation and mitochondrial damage in PO-treated hepatocytes in vitro. Furthermore, we constructed an in vivo NASH murine model by giving a 16-week high fat high cholesterol diet (HFHC) diet to hepatocyte specific GTPBP8-knockout (GTPBP8HKO) mice. We firstly found that HFHC feeding led to metabolic disorder in mice, including high body weight, blood glucose and insulin levels, and liver dysfunctions, which were accelerated in these NASH mice with GTPBP8 deficiency in hepatocytes. Consistently, GTPBP8HKO remarkably exacerbated the progression of NASH phenotypes induced by HFHC, as proved by the anabatic lipid accumulation, inflammation, fibrosis and reactive oxygen species (ROS) production in liver tissues, which could be largely attributed to the severe mitochondrial damage and dysfunction. Mechanistically, we further identified that GTPBP8 interacted with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in hepatocytes. Importantly, the hepaprotective effects of GTPBP8 against mitochondrial dysfunction, oxidative stress and inflammation was largely dependent on PGC-1α expression. Collectively, GTPBP8 may exert a protective role in the progression of NASH, and targeting the GTPBP8/PGC-1α axis may represent a potential strategy for NASH treatment by improving mitochondrial functions.

MiR-31-mediated local translation at the mitotic spindle is important for early development.

miR-31 is a highly conserved microRNA that plays crucial roles in cell proliferation, migration and differentiation. We discovered that miR-31 and some of its validated targets are enriched on the mitotic spindle of the dividing sea urchin embryo and mammalian cells. Using the sea urchin embryo, we found that miR-31 inhibition led to developmental delay correlated with increased cytoskeletal and chromosomal defects. We identified miR-31 to directly suppress several actin remodeling transcripts, including β-actin, Gelsolin, Rab35 and Fascin. De novo translation of Fascin occurs at the mitotic spindle of sea urchin embryos and mammalian cells. Importantly, miR-31 inhibition leads to a significant a increase of newly translated Fascin at the spindle of dividing sea urchin embryos. Forced ectopic localization of Fascin transcripts to the cell membrane and translation led to significant developmental and chromosomal segregation defects, highlighting the importance of the regulation of local translation by miR-31 at the mitotic spindle to ensure proper cell division. Furthermore, miR-31-mediated post-transcriptional regulation at the mitotic spindle may be an evolutionarily conserved regulatory paradigm of mitosis.

14-3-3σ/Stratifin and p21 limit AKT-related malignant progression in skin carcinogenesis following MDM2-associated p53 loss.

To study mechanisms driving/inhibiting skin carcinogenesis, stage-specific expression of 14-3-3σ (Stratifin) was analyzed in skin carcinogenesis driven by activated rasHa/fos expression (HK1.ras/fos) and ablation of PTEN-mediated AKT regulation (K14.creP/Δ5PTENflx/flx). Consistent with 14-3-3σ roles in epidermal differentiation, HK1.ras hyperplasia and papillomas displayed elevated 14-3-3σ expression in supra-basal keratinocytes, paralleled by supra-basal p-MDM2166 activation and sporadic p-AKT473 expression. In bi-genic HK1.fos/Δ5PTENflx/flx hyperplasia, basal-layer 14-3-3σ expression appeared, and alongside p53/p21, was associated with keratinocyte differentiation and keratoacanthoma etiology. Tri-genic HK1.ras/fos-Δ5PTENflx/flx hyperplasia/papillomas initially displayed increased basal-layer 14-3-3σ, suggesting attempts to maintain supra-basal p-MDM2166 and protect basal-layer p53. However, HK1.ras/fos-Δ5PTENflx/flx papillomas exhibited increasing basal-layer p-MDM2166 activation that reduced p53, which coincided with malignant conversion. Despite p53 loss, 14-3-3σ expression persisted in well-differentiated squamous cell carcinomas (wdSCCs) and alongside elevated p21, limited malignant progression via inhibiting p-AKT1473 expression; until 14-3-3σ/p21 loss facilitated progression to aggressive SCC exhibiting uniform p-AKT1473. Analysis of TPA-promoted HK1.ras-Δ5PTENflx/flx mouse skin, demonstrated early loss of 14-3-3σ/p53/p21 in hyperplasia and papillomas, with increased p-MDM2166/p-AKT1473 that resulted in rapid malignant conversion and progression to poorly differentiated SCC. In 2D/3D cultures, membranous 14-3-3σ expression observed in normal HaCaT and SP1ras61 papilloma keratinocytes was unexpectedly detected in malignant T52ras61/v-fos SCC cells cultured in monolayers, but not invasive 3D-cells. Collectively, these data suggest 14-3-3σ/Stratifin exerts suppressive roles in papillomatogenesis via MDM2/p53-dependent mechanisms; while persistent p53-independent expression in early wdSCC may involve p21-mediated AKT1 inhibition to limit malignant progression.

Multivariate Association between Functional Connectivity Gradients and Cognition in Schizophrenia Spectrum Disorders

BackgroundSchizophrenia Spectrum Disorders (SSDs), which are characterized by social cognitive deficits, have been associated with dysconnectivity in “unimodal” (e.g., visual, auditory) and “multimodal” (e.g., default-mode and frontoparietal) cortical networks. However, little is known regarding how such dysconnectivity relates to social and non-social cognition, and how such brain-behavioral relationships associate with clinical outcomes of SSDs. MethodsWe analyzed cognitive (non-social and social) measures and resting-state functional magnetic resonance imaging data from the ‘Social Processes Initiative in Neurobiology of the Schizophrenia(s) (SPINS)’ study (247 stable participants with SSDs and 172 healthy controls, ages 18-55). We extracted gradients from parcellated connectomes and examined the association between the first 3 gradients and the cognitive measures using partial least squares correlation (PLSC). We then correlated the PLSC dimensions with functioning and symptoms in the SSDs group. ResultsThe SSDs group showed significantly lower differentiation on all three gradients. The first PLSC dimension explained 68.53% (p<.001) of the covariance and showed a significant difference between SSDs and Controls (bootstrap p<.05). PLSC showed that all cognitive measures were associated with gradient scores of unimodal and multimodal networks (Gradient 1), auditory, sensorimotor, and visual networks (Gradient 2), and perceptual networks and striatum (Gradient 3), which were less differentiated in SSDs. Furthermore, the first dimension was positively correlated with negative symptoms and functioning in the SSDs group. ConclusionsThese results suggest a potential role of lower differentiation of brain networks in cognitive and functional impairments in SSDs.

Regressivity in public pension systems: The case of Peru

We study the role of income-mortality differentials and pension eligibility conditions on the level of regressivity and progressivity of Peru’s public pension system, using administrative records from 1999 to 2018 to do so. We consider the joint effect of insufficient contributions, by which the poorest contribute to the pension system but ultimately do not qualify for pensions because of insufficient contributions, and differing mortality by socioeconomic status in contributing to regressivity of the system. We find that the impact of insufficient contributions is more important than the impact of higher mortality in making the system regressive.

An atlas of caspase cleavage events in differentiating muscle cells.

Executioner caspases, such as caspase-3, are known to induce apoptosis, but in other contexts, they can control very different fates, including cell differentiation and neuronal plasticity. While hundreds of caspase substrates are known to be specifically targeted during cell death, we know very little about how caspase activity brings about non-apoptotic fates. Here, we report the first proteome identification of cleavage events in C2C12 cells undergoing myogenic differentiation and its comparison to undifferentiated or dying C2C12 cells. These data have identified new caspase substrates, including caspase substrates specifically associated with differentiation, and show that caspases are regulating proteins involved in myogenesis in myotubes, several days after caspase-3 initiated differentiation. Cytoskeletal proteins emerged as a major group of non-apoptotic caspase substrates. We also identified proteins with well-established roles in muscle differentiation as substrates cleaved in differentiating cells.

A Review on Anaplastic Lymphoma Kinase (ALK) Rearrangements and Mutations: Implications for Gastric Carcinogenesis and Target Therapy.

Gastric adenocarcinoma is a complex disease with diverse genetic modifications, including Anaplastic Lymphoma Kinase (ALK) gene changes. The ALK gene is located on chromosome 2p23 and encodes a receptor tyrosine kinase that plays a crucial role in embryonic development and cellular differentiation. ALK alterations can result from gene fusion, mutation, amplification, or overexpression in gastric adenocarcinoma. Fusion occurs when the ALK gene fuses with another gene, resulting in a chimeric protein with constitutive kinase activity and promoting oncogenesis. ALK mutations are less common but can also result in the activation of ALK signaling pathways. Targeted therapies for ALK variations in gastric adenocarcinoma have been developed, including ALK inhibitors that have shown promising results in pre-clinical studies. Future studies are needed to elucidate the ALK role in gastric cancer and to identify predictive biomarkers to improve patient selection for targeted therapy. Overall, ALK alterations are a relevant biomarker for gastric adenocarcinoma treatment and targeted therapies for ALK may improve patients' overall survival.

Fine-Scale Haplotype Mapping Reveals an Association of the FTO Gene with Osteoporosis and Fracture Risk in Postmenopausal Women.

The Fat Mass and Obesity-Associated (FTO) gene encodes a demethylase, which modulates RNA N6-methyladenosine (m6A) and plays a regulatory role in adipocyte differentiation and the pathogenesis of human obesity. To understand the potential role of FTO in osteoporosis (OP), we investigated five single nucleotide variations (SNVs) in intron 1 (rs8057044, rs8050136, rs9939609, rs62033406, and rs9930506) of the FTO gene, and a missense SNV i.e., rs3736228 (A1330V), located in exon 18 of the LRP5 gene, in a cohort of postmenopausal women (n = 188) from Central Europe. Genotyping was performed with an allele discrimination assay, while haplotypes were reconstructed in the population by PHASE 2.1. The rs9930506 was strongly associated with OP (p < 0.0035), which was supported by Bonferroni correction (p < 0.0175), and all SNVs located in the FTO gene were more strongly associated with severe OP with fragility fractures. Among seventeen haplotypes detected for the FTO gene, two haplotypes (H1 and H9) were frequent (frequency > 10%) and distributed in three main haplotypes pairs (H1/H1, H1/H9 and H9/H9, respectively). The pathogenic pair H1/H9 was associated with a leaner phenotype, increased fracture risk, and a lower bone mineral density (BMD), and carried the heterozygous GA of rs9930506, while the protective pair H9/H9 was associated with an increased obesity risk and carried AA alleles of rs9939609. Concordant associations with OP, an increased fracture risk, and a lower BMD at all skeletal sites indicate that the FTO gene is a promising candidate for OP, explaining the complex relationship with obesity and offering new perspectives for the study of the epigenetic regulation of bone metabolism.

Research Progress on Extracellular Matrix Involved in the Development of Preeclampsia.

Preeclampsia (PE) is a serious pregnancy complication, and its primary clinical manifestations are gestational hypertension and proteinuria. Trophoblasts are responsible for the basic functions of the placenta during placental development; recent studies have revealed that placental "shallow implantation" caused by the decreased invasiveness of placental trophoblasts plays a crucial role in PE pathogenesis. The interaction between the cells and the extracellular matrix (ECM) plays a crucial role in trophoblast proliferation, differentiation, and invasion. Abnormal ECM function can result in insufficient migration and invasion of placental trophoblasts, thus participating in PE. This article summarizes the recent studies on the involvement of ECM components, including small leucine-rich proteoglycans, syndecans, glypicans, laminins, fibronectin, collagen, and hyaluronic acid, in the development of PE. ECM plays various roles in PE development, most notably by controlling the activities of trophoblasts. The ECM is structurally stable and can serve as a biological diagnostic marker and therapeutic target for PE.

Differential functional role of Orai1 variants in constitutive Ca2+ entry and calcification in luminal breast cancer cells

Resting cytosolic Ca2+ concentration is tightly regulated to fine-tune Ca2+-dependent cellular functions. Luminal breast cancer cells exhibit constitutive Ca2+ entry mediated by Orai1 and the secretory pathway Ca2+-ATPase, SPCA2, which result in mammary microcalcifications that constitute a prognostic marker of mammary lesions. Two Orai1 isoforms have been identified, the full-length Orai1α, consisting of 301 amino acids, and the short variant, Orai1β, lacking the 63 or 70 N-terminal amino acids comprising residues involved in channel inactivation and binding sites with Orai1 partners. We show that only the mammalian-specific Orai1α rescues SPCA2-dependent constitutive Ca2+ entry in Orai1-knockout MCF7 cells, a widely used luminal breast cancer cell line. FRET analysis and immunoprecipitation revealed that Orai1α shows a greater ability to interact with SPCA2 than Orai1β. Deletion of the first 38 amino acids in Orai1α reduced the interaction with SPCA2 to a similar extent as Orai1β, thus suggesting that the N-terminal 38 amino acids play a relevant role in Orai1α-SPCA2 interaction. Finally, Orai1α, but not Orai1β, rescue the ability of Orai1-deficient cells to form in vitro microcalcifications. These findings provide compelling evidence for a functional role of Orai1α in constitutive Ca2+ entry in MCF7 cells, which might be a target to prevent the development of mammary microcalcifications in luminal breast cancer.

Dual and opposing role of retinoic acid receptor signaling in mesenchymal stem cells for tendon ossification in mice.

Heterotopic ossification is abnormal bone formation in soft tissues that occurs primarily after injury and major surgery. This condition often causes local pain and limits joint motion in the affected limb. Currently, there is no effective treatment or prophylaxis for this condition other than surgical removal of the lesion. Recent studies suggest that retinoic acid receptor (RAR) agonists are effective in suppressing heterotopic ossification in patients with Fibrodysplasia Ossificans Progressiva, a congenital disorder characterized by progressive ossification of soft tissue, by suppressing the aberrant differentiation of mesenchymal stem cells in muscle. In this study, we aimed to elucidate the potential use of RAR agonists in suppressing injury-induced ectopic tendon ossification using a mouse Achilles tenotomy model. Contrary to our initial hypothesis, administration of RAR agonists throughout the experimental period (5 weeks) accelerated ectopic tendon ossification in our model. Of note, in vitro differentiation experiments using tendon-derived mesenchymal stem cells revealed that RAR agonists play opposing roles in osteogenic and chondrogenic differentiation, promoting the former and suppressing the latter. Indeed, we found that RAR agonists suppressed tendon ossification when administered before cartilage nodule formation, but promoted it when administered after. These results suggest that RAR agonists have a dual and opposing effect on tendon ectopic ossification, depending on the duration and timing of their administration. Our data may provide a basis for further investigation of the potential use of RAR agonists in the treatment of injury-induced heterotopic ossification.

MiR-196a Promotes Lipid Deposition in Goat Intramuscular Preadipocytes by Targeting MAP3K1 and Activating PI3K-Akt Pathway.

Meat quality in goats is partly determined by the intramuscular fat (IMF) content, which is associated with the proliferation and differentiation of intramuscular preadipocytes. Emerging studies have suggested that miRNA plays a crucial role in adipocyte proliferation and differentiation. In our recent study, we observed the expression variations in miR-196a in the longissimus dorsi muscle of Jianzhou goats at different ages. However, the specific function and underlying mechanism of miR-196a in IMF deposition are still unclear. This study demonstrated that miR-196a significantly enhanced adipogenesis and apoptosis and reduced the proliferation of preadipocytes. Subsequently, RNA-seq was employed to determine genes regulated by miR-196a, and 677 differentially expressed genes were detected after miR-196a overexpression. The PI3K-Akt pathway was identified as activated in miR-196a regulating intramuscular adipogenesis via Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and further verified via Western blot and rescue assays. Lastly, using RT-qPCR, Western blot, dual-luciferase, and rescue assays, we found that miR-196a promoted adipogenesis and suppressed the proliferation of intramuscular preadipocytes by the downregulation of MAP3K1. In summary, these results suggest that miR-196a regulates IMF deposition by targeting MAP3K1 and activating the PI3K-Akt pathway and provide a theoretical foundation for improving goat meat quality through molecular breeding.

Dopamine and Norepinephrine Differentially Mediate the Exploration-exploitation Tradeoff.

Dopamine (DA) and norepinephrine (NE) have been repeatedly implicated in neuropsychiatric vulnerability, in part via their roles in mediating the decision making processes. Although two neuromodulators share a synthesis pathway and are co-activated under states of arousal, they engage in distinct circuits and modulatory roles. However, the specific role of each neuromodulator in decision making, in particular the exploration-exploitation tradeoff, remains unclear. Revealing how each neuromodulator contributes to exploration-exploitation tradeoff is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. To understand the differences and overlaps of the roles of these two catecholamine systems in regulating exploration, a direct comparison using the same dynamic decision making task is needed. Here, we ran male and female mice in a restless two-armed bandit task, which encourages both exploration and exploitation. We systemically administered a nonselective DA antagonist (flupenthixol), a nonselective DA agonist (apomorphine), a NE beta-receptor antagonist (propranolol), and a NE beta-receptor agonist (isoproterenol), and examined changes in exploration within subjects across sessions. We found a bidirectional modulatory effect of dopamine on exploration. Increasing dopamine activity decreased exploration and decreasing dopamine activity increased exploration. The modulatory effect of beta-noradrenergic receptor activity on exploration was mediated by sex. Reinforcement learning model parameters suggested that dopamine modulation affected exploration via decision noise and norepinephrine modulation affected exploration via sensitivity to outcome. Together, these findings suggested that the mechanisms that govern the exploration-exploitation transition are sensitive to changes in both catecholamine functions and revealed differential roles for NE and DA in mediating exploration.Significance Statement Both dopamine (DA) and norepinephrine (NE) have been implicated in the decision making process. Although these two catecholamines have shared aspects of their biosynthetic pathways and projection targets, they are thought to exert many core functions via distinct neural targets and receptor subtypes. However, the computational neuroscience literature often ascribes similar roles to these catecholamines, despite the above evidence. Resolving this discrepancy is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. This study examines the role of dopamine and norepinephrine on the explore-exploit tradeoff. By testing mice, we were able to compare multiple pharmacological agents within subjects, and examine sources of individual differences, allowing direct comparison between the effects of these two catecholamines in modulating decision making.

Leg Attachment Devices of Tiger Beetles (Coleoptera, Cicindelidae) and Their Relationship to Their Habitat Preferences.

The ability of many insects to adhere vertically or even upside down to smooth substrates is closely related to the morphology and distribution of the adhesive structures on their legs. During locomotion, the legs are in direct contact with different substrates, and it is hypothesized that the adhesive structures have been evolved as an adaption to smooth substrates in specific environments. To investigate whether there is a relationship between the presence of adhesive structures and the combined effects of different environments and mating behavior, we compared five species of tiger beetles belonging to two tribes living in arboreal and non-arboreal environments, respectively. In three non-arboreal species, we found a specific type of adhesive structure consisting of elongated spoon-like setae present on the protarsi of males but absent on the male meso- and metatarsi and on females. In Tricondyla pulchripes, an arboreal species living on stems, we found three types of adhesive setae on male protarsi, while only two types of setae were found on male meso- and metatarsi and on females. In Neocollyris linearis, an arboreal species living on leaves, we found three types of adhesive setae on male pro-, meso- and meta-tarsi but only two types of adhesive setae on females. The adaptive evolution of these adhesive structures was probably driven by the selective pressures of both mating behavior and the presence of smooth substrates in the respective environments. It is discussed that the adhesive structures in tiger beetles may be an adaptive evolutionary response to the plant surfaces and may play an important role in species differentiation.