The transcription factor ZNF469 regulates collagen production in liver fibrosis.

Non-alcoholic fatty liver disease (NAFLD) - characterized by excess accumulation of fat in the liver - now affects one third of the world's population. As NAFLD progresses, extracellular matrix components including collagen accumulate in the liver causing tissue fibrosis, a major determinant of disease severity and mortality. To identify transcriptional regulators of fibrosis, we computationally inferred the activity of transcription factors (TFs) relevant to fibrosis by profiling the matched transcriptomes and epigenomes of 108 human liver biopsies from a deeply-characterized cohort of patients spanning the full histopathologic spectrum of NAFLD. CRISPR-based genetic knockout of the top 100 TFs identified ZNF469 as a regulator of collagen expression in primary human hepatic stellate cells (HSCs). Gain- and loss-of-function studies established that ZNF469 regulates collagen genes and genes involved in matrix homeostasis through direct binding to gene bodies and regulatory elements. By integrating multiomic large-scale profiling of human biopsies with extensive experimental validation we demonstrate that ZNF469 is a transcriptional regulator of collagen in HSCs. Overall, these data nominate ZNF469 as a previously unrecognized determinant of NAFLD-associated liver fibrosis.

Piezo1 expression in chondrocytes controls endochondral ossification and osteoarthritis development.

Piezo proteins are mechanically activated ion channels, which are required for mechanosensing functions in a variety of cell types. While we and others have previously demonstrated that the expression of Piezo1 in osteoblast lineage cells is essential for bone-anabolic processes, there was only suggestive evidence indicating a role of Piezo1 and/or Piezo2 in cartilage. Here we addressed the question if and how chondrocyte expression of the mechanosensitive proteins Piezo1 or Piezo2 controls physiological endochondral ossification and pathological osteoarthritis (OA) development. Mice with chondrocyte-specific inactivation of Piezo1 (Piezo1Col2a1Cre), but not of Piezo2, developed a near absence of trabecular bone below the chondrogenic growth plate postnatally. Moreover, all Piezo1Col2a1Cre animals displayed multiple fractures of rib bones at 7 days of age, which were located close to the growth plates. While skeletal growth was only mildly affected in these mice, OA pathologies were markedly less pronounced compared to littermate controls at 60 weeks of age. Likewise, when OA was induced by anterior cruciate ligament transection, only the chondrocyte inactivation of Piezo1, not of Piezo2, resulted in attenuated articular cartilage degeneration. Importantly, osteophyte formation and maturation were also reduced in Piezo1Col2a1Cre mice. We further observed increased Piezo1 protein abundance in cartilaginous zones of human osteophytes. Finally, we identified Ptgs2 and Ccn2 as potentially relevant Piezo1 downstream genes in chondrocytes. Collectively, our data do not only demonstrate that Piezo1 is a critical regulator of physiological and pathological endochondral ossification processes, but also suggest that Piezo1 antagonists may be established as a novel approach to limit osteophyte formation in OA.

Fracture healing research: Recent insights.

Bone has the rare capability of scarless regeneration that enables the complete restoration of the injured bone area. In recent decades, promising new technologies have emerged from basic, translational and clinical research for fracture treatment; however, 5-10 % of all bone fractures still fail to heal successfully or heal in a delayed manner. Several comorbidities and risk factors have been identified which impair bone healing and might lead to delayed bone union or non-union. Therefore, a considerable amount of research has been conducted to elucidate molecular mechanisms of successful and delayed fracture healing to gain further insights into this complex process. One focus of recent research is to investigate the complex interactions of different cell types and the action of progenitor cells during the healing process. Of particular interest is also the identification of patient-specific comorbidities and how these affect fracture healing. In this review, we discuss the recent knowledge about progenitor cells for long bone repair and the influence of comorbidities such as diabetes, postmenopausal osteoporosis, and chronic stress on the healing process. The topic selection for this review was made based on the presented studies at the 2022 annual meeting of the European Calcified Tissue Society (ECTS) in Helsinki.

Avaliação microbiológica de queijos tipo Minas Frescal artesanal, comercializados no Mercado Municipal de Campo Grande, Mato Grosso do Sul, 2000 / Microbiological evaluation of fresh handmade Minas cheese commercialized at Municipal Market in Campo Grande, Mato Grosso do Sul, 2000

Foram analisadas vinte (20) amostras de queijo tipo "Minas" frescal, comercializadas no Mercado Municipal, produzidos em vários municípios do Estado, no período de outubro a novembro de 2000. Os parâmetros microbiológicos pesquisados foram: Coliformes fecais, Salmonella sp, Escherichia coli e Staphylococcus aureus, através da metodologia do Compedium of Methods for the Microbiological Examination of Foods (APHA, 1984) e do Instituto Adolfo Lutz (IAL). De acordo com a Portaria 451 de 19 de setembro de 1997 - Ministério da Saúde, apenas duas (02) amostras apresentaram resultados aceitáveis para consumo humano. O resultado obtido é um alerta às autoridades sanitárias em relação à produção e ao comércio deste produto, diante do risco à saúde do consumidor.