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Hephaestin is a vertebrate multicopper ferroxidase important for the transfer of dietary iron from intestinal cells to the blood. Hephaestin is mutated in the sex-linked anemia mouse, resulting in iron deficiency. However, sex-linked anemia mice still retain some hephaestin ferroxidase activity. They survive, breed, and their anemia improves with age. To gain a better understanding of the role of hephaestin in iron homeostasis, we used the Cre-lox system to generate knockout mouse models with whole body or intestine-specific (Villin promoter) ablation of hephaestin. Both types of mice were viable, indicating that hephaestin is not essential and that other mechanisms, multicopper ferroxidase-dependent or not, must compensate for hephaestin deficiency. The knockout strains, however, both developed a microcytic, hypochromic anemia, suggesting severe iron deficiency and confirming that hephaestin plays an important role in body iron acquisition. Consistent with this, the knockout mice accumulated iron in duodenal enterocytes and had reduced intestinal iron absorption. In addition, the similarities of the phenotypes of the whole body and intestine-specific hephaestin knockout mice clarify the important role of hephaestin specifically in intestinal enterocytes in maintaining whole body iron homeostasis. These mouse models will serve as valuable tools to study the role of hephaestin and associated proteins in iron transport in the small intestine and other tissues.

Iron is crucial for many biological functions, but quantitatively the most important use of iron is in the production of hemoglobin in red blood cell precursors. The amount of iron in the plasma, and hence its availability for hemoglobin synthesis, is determined by the liver-derived iron regulatory hormone hepcidin. When the iron supply to erythroid precursors is limited, as often occurs during stimulated erythropoiesis, these cells produce signals to inhibit hepatic hepcidin production, thereby increasing the amount of iron that enters the plasma. How stimulated erythropoiesis suppresses hepcidin production is incompletely understood, but erythroferrone, Gdf15 and Twsg1 have emerged as candidate regulatory molecules. To further examine the relationship between erythropoiesis and the candidate erythroid regulators, we have studied five mouse models of anemia, including two models of β-thalassemia (Hbbth3/+ and RBC14), the hemoglobin deficit mouse (hbd), dietary iron deficient mice and mice treated with phenylhydrazine to induce acute hemolysis. Hematological parameters, iron status and the expression of Erfe (the gene encoding erythroferrone), Gdf15 and Twsg1 in the bone marrow and spleen were examined. Erfe expression was the most consistently upregulated of the candidate erythroid regulators in all of the mouse models examined. Gene expression was particularly high in the bone marrow and spleen of iron deficient animals, making erythroferrone an ideal candidate erythroid regulator, as its influence is strongest when iron supply to developing erythroid cells is limited. Gdf15 expression was also upregulated in most of the anemia models studied although the magnitude of the increase was generally less than that of Erfe. In contrast, very little regulation of Twsg1 was observed. These results support the prevailing hypothesis that erythroferrone is a promising erythroid regulator and demonstrate that Erfe expression is stimulated most strongly when the iron supply to developing erythroid cells is compromised.

Oxygenase-catalysed post-translational modifications of basic protein residues, including lysyl hydroxylations and N ε -methyl lysyl demethylations, have important cellular roles. Jumonji-C (JmjC) domain-containing protein 5 (JMJD5), which genetic studies reveal is essential in animal development, is reported as a histone N ε -methyl lysine demethylase (KDM). Here we report how extensive screening with peptides based on JMJD5 interacting proteins led to the finding that JMJD5 catalyses stereoselective C-3 hydroxylation of arginine residues in sequences from human regulator of chromosome condensation domain-containing protein 1 (RCCD1) and ribosomal protein S6 (RPS6). High-resolution crystallographic analyses reveal overall fold, active site and substrate binding/product release features supporting the assignment of JMJD5 as an arginine hydroxylase rather than a KDM. The results will be useful in the development of selective oxygenase inhibitors for the treatment of cancer and genetic diseases. Jumonji-C domain containing protein 5 (JMJD5) is essential for animal development but its catalytic activity has remained elusive so far. Here the authors show that human JMJD5 is an arginyl-hydroxylase and present the cofactor, substrate and product bound JMJD5 crystal structures.

To describe the epidemiology and patterns of gymnastics-related Head & Neck trauma injuries using the NEISS database from 2001 to 2020. Cross-sectional analysis of a national database. Gymnastics-related ED visits between 2001 and 2020 were queried from the NEISS database. Bivariate chi-squared analyses were used to compare injury demographics, location, type, and disposition. Fracture location was identified using the narrative description of each case and were divided into subtypes for further analysis. 1455 gymnastics-related head and neck traumatic injuries were identified. The majority were in females (65.8%). The most common presenting age group was pediatric (≤18 years) (92.7%), and the largest racial group was Caucasian (51.5%). Of all location subtypes, facial injuries were the most common presenting injury type overall (45.2%). Regarding injury types, lacerations were most common (36.8%), followed by dental injury (30.7%) and fractures (21.2%). The most common location of head and neck fractures was the nose (45.8%), followed by cervical spine (16.7%) and orbit (13.3%). The majority (95.7%) of gymnastics-related head and neck traumatic injuries presenting to the ED were treated and discharged. This study characterizes gymnastics-related head and neck injuries which is a topic that is under-studied. The findings from this study are helpful for gymnasts and those who care for them including providers, coaches and guardians, and this data may help inform future guidelines for treatment and injury prevention.

Tumours exist in a hypoxic microenvironment and must limit excessive oxygen consumption. Hypoxia-inducible factor (HIF) controls mitochondrial oxygen consumption, but how/if tumours regulate non-mitochondrial oxygen consumption (NMOC) is unknown. Protein-tyrosine phosphatase-1B (PTP1B) is required for Her2/Neu -driven breast cancer (BC) in mice, although the underlying mechanism and human relevance remain unclear. We found that PTP1B-deficient HER2 + xenografts have increased hypoxia, necrosis and impaired growth. In vitro , PTP1B deficiency sensitizes HER2 + BC lines to hypoxia by increasing NMOC by α-KG-dependent dioxygenases (α-KGDDs). The moyamoya disease gene product RNF213, an E3 ligase, is negatively regulated by PTP1B in HER2 + BC cells. RNF213 knockdown reverses the effects of PTP1B deficiency on α-KGDDs, NMOC and hypoxia-induced death of HER2 + BC cells, and partially restores tumorigenicity. We conclude that PTP1B acts via RNF213 to suppress α-KGDD activity and NMOC. This PTP1B/RNF213/α-KGDD pathway is critical for survival of HER2 + BC, and possibly other malignancies, in the hypoxic tumour microenvironment. Banh et al. show that PTP1B decreases non-mitochondrial oxygen consumption by regulating the RNF213/α-KGDD pathway, thus promoting hypoxic survival of cancer cells.

Iron deficiency is one of the most common nutritional deficiencies worldwide and is often treated with oral iron supplements. However, commonly used supplements, including those based on ferrous iron salts, are associated with gastrointestinal side effects and unfavorable changes in the intestinal microbiome. Sucrosomial® iron is a novel iron formulation that is effective at treating iron deficiency, and with fewer gastrointestinal side effects, yet its effect on the gut microbiome has not been examined previously. Thus, we treated mice for two weeks with diets containing either Sucrosomial® iron or ferrous sulfate as the sole iron source and examined bacterial communities in the intestine using 16S Microbial Profiling of DNA extracted from feces collected both prior to and following dietary treatment. Mice treated with Sucrosomial® iron showed an increase in Shannon diversity over the course of the study. This was associated with a decrease in the abundance of the phylum Proteobacteria, which contains many pathogenic species, and an increase in short chain fatty acid producing bacteria such as Lachnospiraceae, Oscillibacter and Faecalibaculum. None of these changes were observed in mice treated with ferrous sulfate. These results suggest that Sucrosomial® iron may have a beneficial effect on the intestinal microbiome when compared to ferrous sulfate and that this form of iron is a promising alternative to ferrous iron salts for the treatment of iron deficiency.

Tudor Interacting Repair Regulator (TIRR) is an RNA-binding protein (RBP) that interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. We utilized iCLIP to identify RNAs that directly bind to TIRR within cells, identifying the long non-coding RNA NEAT1 as the primary RNA partner. The high affinity of TIRR for NEAT1 is due to prevalent G-rich motifs in the short isoform (NEAT1_1) region of NEAT1. This interaction destabilizes the TIRR/53BP1 complex, promoting 53BP1’s function. NEAT1_1 is enriched during the G1 phase of the cell cycle, thereby ensuring that TIRR-dependent inhibition of 53BP1’s function is cell cycle-dependent. TDP-43, an RBP that is implicated in neurodegenerative diseases, modulates the TIRR/53BP1 complex by promoting the production of the NEAT1 short isoform, NEAT1_1. Together, we infer that NEAT1_1, and factors regulating NEAT1_1, may impact 53BP1-dependent DNA repair processes, with implications for a spectrum of diseases. TIRR interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. Here, the authors show that the lncRNA NEAT1, regulated by TDP-43, destabilizes the TIRR/53BP1 complex in G1, promoting 53BP1’s function in DSB repair and p53 transactivation.

OLE (ornate, large, extremophilic) RNAs comprise a class of structured noncoding RNAs (ncRNAs) found in many extremophilic bacteria species. OLE RNAs constitute one of the longest and most widespread bacterial ncRNA classes whose major biochemical function remains unknown. In the Gram-positive alkaliphile Bacillus halodurans, OLE RNA is abundant, and localizes to the cell membrane by association with the transmembrane OLE-associated protein called OapA (formerly OAP). These characteristics, along with the well-conserved sequence and structural features of OLE RNAs, suggest that the OLE ribonucleoprotein (RNP) complex performs important biological functions. B. halodurans strains lacking OLE RNA (Δole) or OapA (ΔoapA) are less tolerant of cold (20 °C) and short-chain alcohols (e.g., ethanol). Here, we describe the effects of a mutant OapA (called PM1) that more strongly inhibits growth under cold or ethanol stress compared with strains lacking the oapA gene, even when wild-type OapA is present. This dominant-negative effect of PM1 is reversed by mutations that render OLE RNA nonfunctional. This finding demonstrates that the deleterious PM1 phenotype requires an intact RNP complex, and suggests that the complex has one or more additional undiscovered components. A genetic screen uncovered PM1 phenotype suppressor mutations in the ybzG gene, which codes for a putative RNA-binding protein of unknown biological function. We observe that YbzG protein (also called OapB) selectively binds OLE RNA in vitro, whereas a mutant version of the protein is not observed to bind OLE RNA. Thus, YbzG/OapB is an important component of the functional OLE RNP complex in B. halodurans.

The rise in the numbers of religious \"nones\" is an almost universal phenomenon across the Western world. The purpose of this study is to explore the extent to which religious nones are socialized to adopt a \"no religion\" position as children, as compared with disaffiliating during their teen or adult years. Related, among those religious nones who come from a religious background, we examine the timing and depth of a person's disaffiliation. This study sheds light on these issues by combining a quantitative analysis of religious nones samples in Alberta, Canada, America, and other international contexts with a qualitative analysis of 30 semistructured interviews with religious nones. Building on a stage of decline framework, we argue that while disaffiliation has been a lead catalyst for the growth among the religious none population—and we offer several observations of what fuels disaffiliation—moving forward we can and should expect irreligious socialization to gradually take the lead in explaining rising religious none figures.

Objective To investigate the possibility of hydroxyapatite as a safe and effective alternative to currently used bioavailable materials for repair of tegmen defects and labyrinthine fistulas in the setting of cholesteatoma. Study Design Retrospective study. Setting Tertiary‐level‐care hospital. Methods Electronic medical records of patients 18+ years undergoing cholesteatoma‐removal surgery between 2013 and 2022 were reviewed. Results Twenty‐two patients diagnosed with cholesteatoma who underwent repair of either a tegmen defect or labyrinthine fistula using hydroxyapatite were evaluated. There were 17 canal wall up (CWU) and 5 canal wall down (CWD) surgeries. The cholesteatoma recidivism rate was 18.2% (n = 4) and the recurrence rate was 4.5% (n = 1). To ensure that these rates were similar to cholesteatoma‐removal surgeries in which hydroxyapatite was not used, a 22 age, gender, and operative technique‐matched cohort was evaluated. For patients with CWU surgeries, the rate of recurrence and recidivism were identical between both cohorts (0% and 23.5%, respectively; P = 1 for both). While in CWD surgeries, there was a nonstatistically significant difference in the recurrence as there was only 1 patient with recurrence in the hydroxyapatite group (P = 1). Three (13.5%) patients in the hydroxyapatite group had a local infection and 1 (4.5%) had a subacute mastoid infection. All patients with semicircular canal fistulas had consistent bone lines on postoperative audiograms, with no worsening sensorineural hearing loss. Conclusion In our cohort, hydroxyapatite was safe and successful in repairing skull base defects and inner‐ear fistulas in the setting of cholesteatoma with a low rate of postoperative infection and no evidence of a higher rate of cholesteatoma recurrence. Further studies are needed to assess population generalizability.