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Microplastics are a subject of growing interest as they are a potential threat for living organisms. Textile microfibers (MFs) are an important microplastics sub-group that have been reported as a major source of microplastics release into the environment. This pollution occurs mainly during the washing of synthetic garments. However, standardized methods to quantify and characterize these MFs are scarce. This study proposes a new analytical protocol to characterize these MFs in number and size by means of filtration techniques, optical and electronic microscopy and automatic image post-processing. This approach was developed and validated on effluents from washing machines produced in different conditions (5 different garments, sequential cycles, and presence or not of detergent). Among the analyzed effluents, it was found that 40 to 75% of microfibers have a length comprised between 50 and 200 μm, with average microfiber diameters ranging from 8 to 17 μm depending on the type of textile. The emission range of microfibers was estimated to be between 220,000 to 2,820,000 microfibers per kg of textile depending on the type of garment and the washing conditions. The counting method developed is adapted to a certain range of textiles, such as 100% polyester fleece jackets (PET-1), 100% smooth polyester T-shirt (PET-2) and 100% acrylic sweater (PAN), and is not affected by the presence of detergent. The proposed method of characterization of these MFs lengths can also be extrapolated to the counting of other objects that have a similar morphology to the analyzed fibers. Hence, it can be helpful to develop new testing capture technologies and, thus, contribute to the enhancement of filtering techniques of several pollutants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Fibroblast growth factor (FGF10)-mediated signals are essential for embryonic eyelid closure in mammals. Systemic SOX11-deficient mice are born with unclosed eyelids, suggesting a possible role of SOX11 in eyelid closure. However, the underlying mechanisms of this process remain unclear. In this study, we show that epithelial deficiency of SOX11 causes a defect in the extension of the leading edge of the eyelid, leading to failure of embryonic eyelid closure. c-Jun in the eyelid is a transcription factor downstream of FGF10 required for the extension of the leading edge of the eyelid, and c-Jun level was decreased in epithelial SOX11-deficient embryos. These results suggest that epithelial SOX11 plays an important role in embryonic eyelid closure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

SOX9 plays an important role in chondrocyte differentiation and, in the developing axial skeleton, maintains the notochord and the demarcation of intervertebral disc compartments. Diminished expression is linked to campomelic dysplasia, resulting in severe scoliosis and progressive disc degeneration. However, the specific functions of SOX9 in the adult spinal column and disc are largely unknown. Accordingly, employing a strategy to conditionally delete Sox9 in Acan-expressing cells (Acan CreERT2 Sox9 fl/ f l ), we delineated these functions in the adult intervertebral disc. Acan CreERT2 Sox9 fl/ f l mice (Sox9 cKO ) showed extensive and progressive remodeling of the extracellular matrix in nucleus pulposus (NP) and annulus fibrosus (AF), consistent with human disc degeneration. Progressive degeneration of the cartilaginous endplates (EP) was also evident in Sox9 cKO mice, and it preceded morphological changes seen in the NP and AF compartments. Fate mapping using tdTomato reporter, EdU chase, and quantitative immunohistological studies demonstrated that SOX9 is crucial for disc cell survival and phenotype maintenance. Microarray analysis showed that Sox9 regulated distinct compartment-specific transcriptomic landscapes, with prominent contributions to the ECM, cytoskeleton-related, and metabolic pathways in the NP and ion transport, the cell cycle, and signaling pathways in the AF. In summary, our work provides new insights into disc degeneration in Sox9 cKO mice at the cellular, molecular, and transcriptional levels, underscoring tissue-specific roles of this transcription factor. Our findings may direct future cell therapies targeting SOX9 to mitigate disc degeneration., Competing Interests: Declaration of Competing Interest R.A. Barve may receive royalty income based on the CompBio technology developed by R.A. Barve and licensed by Washington University to PercayAI. The remaining authors declare they have no competing interests to disclose in relation to the contents of this article., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved., Methods: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated., Results: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated., Conclusions: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.

SOX9 is a pivotal transcription factor in chondrocytes, a lineage essential in skeletogenesis. Its mandatory role in transactivating many cartilage-specific genes is well established, whereas its pioneer role in lineage specification, which along with transactivation defines master transcription factors, remains to be better defined. Abundant, but yet incomplete evidence exists that intricate molecular networks control SOX9 activity during the multi-step chondrogenesis pathway. They include a highly modular genetic regulation, post-transcriptional and post-translational modifications, and varying sets of functional partners. Fully uncovering SOX9 actions and regulation is fundamental to explain mechanisms underlying many diseases that directly or indirectly affect SOX9 activities and to design effective disease treatments. We here review current knowledge, highlight recent discoveries, and propose new research directions to answer remaining questions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The Sox4 transcription factor mediates early B-cell differentiation. Compared with normal pre-B cells, SOX4 promoter regions in Ph(+) ALL cells are significantly hypomethylated. Loss and gain-of-function experiments identified Sox4 as a critical activator of PI3K/AKT and MAPK signaling in ALL cells. ChIP experiments confirmed that SOX4 binds to and transcriptionally activates promoters of multiple components within the PI3K/AKT and MAPK signaling pathways. Cre-mediated deletion of Sox4 had little effect on normal pre-B cells but compromised proliferation and viability of leukemia cells, which was rescued by BCL2L1 and constitutively active AKT and p110 PI3K. Consistent with these findings, high levels of SOX4 expression in ALL cells at the time of diagnosis predicted poor outcome in a pediatric clinical trial (COG P9906). Collectively, these studies identify SOX4 as a central mediator of oncogenic PI3K/AKT and MAPK signaling in ALL.

The mechanisms underlying synovial joint development remain poorly understood. Here we use complete and cell-specific gene inactivation to identify the roles of the redundant chondrogenic transcription factors Sox5 and Sox6 in this process. We show that joint development aborts early in complete mutants (Sox5(-/-)6(-/-)). Gdf5 and Wnt9a expression is punctual in articular progenitor cells, but Sox9 downregulation and cell condensation in joint interzones are late. Joint cell differentiation is unsuccessful, regardless of lineage, and cavitation fails. Sox5 and Sox6 restricted expression to chondrocytes in wild-type embryos and continued Erg expression and weak Ihh expression in Sox5(-/-)6(-/-) growth plates suggest that growth plate failure contribute to this Sox5(-/-)6(-/-) joint morphogenesis block. Sox5/6 inactivation in specified joint cells and chondrocytes (Sox5(fl/fl)6(fl/fl)Col2Cre) also results in a joint morphogenesis block, whereas Sox5/6 inactivation in specified joint cells only (Sox5(fl/fl)6(fl/fl)Gdf5Cre) results in milder joint defects and normal growth plates. Sox5(fl/fl)6(fl/fl)Gdf5Cre articular chondrocytes remain undifferentiated, as shown by continued Gdf5 expression and pancartilaginous gene downregulation. Along with Prg4 downregulation, these defects likely account for joint tissue overgrowth and incomplete cavitation in adult mice. Together, these data suggest that synovial joint morphogenesis relies on essential roles for Sox5/6 in promoting both growth plate and articular chondrocyte differentiation., (Copyright 2010 Elsevier Inc. All rights reserved.)

Sox5, Sox6, and Sox13 constitute the group D of sex-determining region (Sry)-related transcription factors. They are highly conserved in the family-specific high-mobility-group (HMG) box DNA-binding domain and in a group-specific coiled-coil domain. The latter mediates SoxD protein dimerization and thereby preferential binding to pairs of DNA recognition sites. The SoxD genes have overlapping expression and cell-autonomously control discrete lineages. Sox5 and Sox6 redundantly enhance chondrogenesis, but retard gliogenesis. Sox5 hinders melanogenesis, promotes neural crest generation, and controls the pace of neurogenesis. Sox6 promotes erythropoiesis, and Sox13 modulates T cell specification and is an autoimmune antigen. SoxD proteins enhance transactivation by Sox9 in chondrocytes, but antagonize Sox9 and other SoxE proteins in oligodendrocytes and melanocytes, and also repress transcription through various mechanisms in several other lineages. While their biological and molecular functions remain incompletely understood, the SoxD proteins have thus already proven that they critically modulate cell fate in major lineages., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Maintain stemness, commit to a specific lineage, differentiate, proliferate, or die. These are essential decisions that every cell is constantly challenged to make in multi-cellular organisms to ensure proper development, adult maintenance, and adaptability. SRY-related high-mobility-group box (Sox) transcription factors have emerged in the animal kingdom to help cells effect such decisions. They are encoded by 20 genes in humans and mice. They share a highly conserved high-mobility-group box domain that was originally identified in SRY, the sex-determining gene on the Y chromosome, and that has derived from a canonical high-mobility-group domain characteristic of chromatin-associated proteins. The high-mobility-group box domain binds DNA in the minor groove and increases its DNA binding affinity and specificity by interacting with many types of transcription factors. It also bends DNA and may thereby confer on Sox proteins a unique and critical role in the assembly of transcriptional enhanceosomes. Sox proteins fall into eight groups. Most feature a transactivation or transrepression domain and thereby also act as typical transcription factors. Each gene has distinct expression pattern and molecular properties, often redundant with those in the same group and overlapping with those in other groups. As a whole the Sox family controls cell fate and differentiation in a multitude of processes, such as male differentiation, stemness, neurogenesis, and skeletogenesis. We review their specific molecular properties and in vivo roles, stress recent advances in the field, and suggest directions for future investigations.

Erythropoiesis, the essential process of hematopoietic stem cell development into erythrocytes, is controlled by lineage-specific transcription factors that determine cell fate and differentiation and by the hormone erythropoietin that stimulates cell survival and proliferation. Here we identify the Sry-related high-mobility-group (HMG) box transcription factor Sox6 as an important enhancer of definitive erythropoiesis. Sox6 is highly expressed in proerythroblasts and erythroblasts in the fetal liver, neonatal spleen, and bone marrow. Mouse fetuses and pups lacking Sox6 develop erythroid cells slowly and feature misshapen, short-lived erythrocytes. They compensate for anemia by elevating the serum level of erythropoietin and progressively enlarging their erythropoietic tissues. Erythroid-specific inactivation of Sox6 causes the same phenotype, demonstrating cell-autonomous roles for Sox6 in erythroid cells. Sox6 potentiates the ability of erythropoietin signaling to promote proerythroblast survival and has an effect additive to that of erythropoietin in stimulating proerythroblast and erythroblast proliferation. Sox6 also critically facilitates erythroblast and reticulocyte maturation, including hemoglobinization, cell condensation, and enucleation, and ensures erythrocyte cytoskeleton long-term stability. It does not control adult globin and erythrocyte cytoskeleton genes but acts by stabilizing filamentous actin (F-actin) levels. Sox6 thus enhances erythroid cell development at multiple levels and thereby ensures adequate production and quality of red blood cells.

Background/aims: Treatment of chronic hepatitis C with interferon can be ineffective due to relapse. We aimed to reduce the 40% relapse rate of 6 months interferon-ribavirin combination therapy by prolonging treatment to 18 months., Methods: Three hundred patients with treatment-naive hepatitis C, were randomized to 18 months combination therapy with interferon (3MU tiw) and ribavirin (1000-1200 mg/day), 18 months interferon combined with placebo, or 6 months combination therapy with interferon and ribavirin, in a double blinded manner. All 295 patients who received at least one dose of treatment were included in the intention to treat analysis., Results: At the end of treatment, HCV RNA was undetectable in 55 and 49% of those on 6 and 18 months combination therapy, respectively, versus 26% of those on monotherapy (P<0.001). The relapse rate was 38% for 6 months combination therapy, 38% for 18 months monotherapy, and only 13% for 18 months combination treatment (P=0.002). The sustained response rates were 34% for 6 months combination therapy, 16% for 18 months monotherapy and 43% for 18 months combination therapy (P<0.05)., Conclusions: Reduction of relapse rates to 15% or less is feasible by prolongation of interferon-ribavirin treatment to 18 months.