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1.
Methicillin‐resistant Staphylococcus aureus eradication in young infants should include the diaper area and treat housing contacts
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2.
Se-Jin Lee Adam Lehar Yewei Liu Chi Hai Ly Quynh-Mai Pham Michael Michaud Renata Rydzik Daniel W. Youngstrom Michael M. Shen Vesa Kaartinen Emily L. Germain-Lee Thomas A. Rando 《Proceedings of the National Academy of Sciences of the United States of America》2020,117(49):30907
Myostatin (MSTN) is a transforming growth factor-β (TGF-β) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-β family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting signaling in myofibers is sufficient to cause significant increases in muscle mass, showing that myofibers are the direct target for signaling by these ligands in the regulation of muscle growth. Moreover, we show that there is functional redundancy between the two type II receptors as well as between the two type I receptors and that all four type II/type I receptor combinations are utilized in vivo. Targeting signaling specifically in myofibers also led to reductions in overall body fat content and improved glucose metabolism in mice fed either regular chow or a high-fat diet, demonstrating that these metabolic effects are the result of enhanced muscling. We observed no effect, however, on either bone density or muscle regeneration in mice in which signaling was targeted in myofibers. The latter finding implies that MSTN likely signals to other cells, such as satellite cells, in addition to myofibers to regulate muscle homeostasis.Myostatin (MSTN) is a secreted signaling molecule that normally acts to limit skeletal muscle growth (for review, see ref. 1). Mice lacking MSTN exhibit dramatic increases in muscle mass throughout the body, with individual muscles growing to about twice the normal size (2). MSTN appears to play two distinct roles in regulating muscle size, one to regulate the number of muscle fibers that are formed during development and a second to regulate the growth of those fibers postnatally. The sequence of MSTN has been highly conserved through evolution, with the mature MSTN peptide being identical in species as divergent as humans and turkeys (3). The function of MSTN has also been conserved, and targeted or naturally occurring mutations in MSTN have been shown to cause increased muscling in numerous species, including cattle (3–5), sheep (6), dogs (7), rabbits (8), rats (9), swine (10), goats (11), and humans (12). Numerous pharmaceutical and biotechnology companies have developed biologic agents capable of blocking MSTN activity, and these have been tested in clinical trials for a wide range of indications, including Duchenne and facioscapulohumeral muscular dystrophy, inclusion body myositis, muscle atrophy following falls and hip fracture surgery, age-related sarcopenia, Charcot–Marie–Tooth disease, and cachexia due to chronic obstructive pulmonary disease, end-stage kidney disease, and cancer.The finding that certain inhibitors of MSTN signaling can increase muscle mass even in Mstn−/− mice revealed that the function of MSTN as a negative regulator of muscle mass is partially redundant with at least one other TGF-β family member (13, 14), and subsequent studies have identified activin A as one of these cooperating ligands (15, 16). MSTN and activin A share many key regulatory and signaling components. For example, the activities of both MSTN and activin A can be modulated extracellularly by naturally occurring inhibitory binding proteins, including follistatin (17, 18) and the follistatin-related protein, FSTL-3 or FLRG (19, 20). Moreover, MSTN and activin A also appear to share receptor components. Based on in vitro studies, MSTN is capable of binding initially to the activin type II receptors, ACVR2 and ACVR2B (also called ActRIIA and ActRIIB) (18) followed by engagement of the type I receptors, ALK4 and ALK5 (21). In previous studies, we presented genetic evidence supporting a role for both ACVR2 and ACVR2B in mediating MSTN signaling and regulating muscle mass in vivo. Specifically, we showed that mice expressing a truncated, dominant-negative form of ACVR2B in skeletal muscle (18) or carrying deletion mutations in Acvr2 and/or Acvr2b (13) have significantly increased muscle mass. One limitation of the latter study, however, was that we could not examine the consequence of complete loss of both receptors using the deletion alleles, as double homozygous mutants die early during embryogenesis (22). Moreover, the roles that the two type I receptors, ALK4 and ALK5, play in regulating MSTN and activin A signaling in muscle in vivo have not yet been documented using genetic approaches. Here, we present the results of studies in which we used floxed alleles for each of the type II and type I receptor genes in order to target these receptors alone and in combination in muscle fibers. We show that these receptors are functionally redundant and that signaling through each of these receptors contributes to the overall control of muscle mass. 相似文献
3.
Several V genes participate in the early phenyloxazolone response in various combinations 总被引:4,自引:0,他引:4
Seventeen monoclonal anti-2-phenyloxazolone antibodies from the early (day 7) primary response were partially sequenced with an mRNA method. Ten antibodies expressed the VH-Ox1 gene. The remaining seven express at least four but probably six different germ-line VH genes belonging to Dildrop's groups 1, 5, 6 and 7 (Immunol. Today 1984. 5: 85). Two of them have been met before in other antibodies, one (group 6) in J606 and the other (group 7) in antibodies to the influenza virus hemagglutinin. Eleven kappa chains were partially sequenced and five of them (all VH-Ox1 antibodies) express the V kappa-Ox1 gene. One expresses another germ-line gene of the V kappa-Ox1 family, one the V kappa 89.4 gene, three the V kappa 45.1 gene and one a new V kappa gene. The V kappa 45.1 gene was found to form anti-phOx antibodies with two new VH genes. The frequency of somatic mutations in day 7 antibodies was estimated by comparing germ-line sequences and antibody sequences. It is low (one mutation per 2500 nucleotides sequenced), twenty times lower than in antibodies obtained a week later. Two anti-idiotype antisera (495 and 260) are useful in the typing of monoclonal antibodies. 260 bound only to antibodies coded by both VH-Ox1 and V kappa-Ox1 genes. 495 bound strongly to antibodies coded by the VH-Ox1 gene and weakly to antibodies coded by the (related) VH101 gene regardless of the light chain partner. 相似文献
4.
Ignacio Gonzalez-Gomez Ilkka Mononen Nora Heisterkamp John Groffen Vesa Kaartinen 《The American journal of pathology》1998,153(4):1293-1300
Aspartylglycosaminuria (AGU) is one of the most common lysosomal storage disorders in humans. A mouse model for AGU has been recently generated through targeted disruption of the glycosylasparaginase gene, and at a young age the glycosyl asparaginase-deficient mice demonstrated many pathological changes found in human AGU patients (Kaartinen V, Mononen I, Voncken J-W, Gonzalez-Gomez I, Heisterkamp N, Groffen J: A mouse model for aspartylglycosaminuria. Nat Med 1996, 2:1375–1378). Our current findings demonstrate that after the age of 10 months, the general condition of null mutant mice gradually deteriorated. They suffered from a progressive motoric impairment and impaired bladder function and died prematurely. A widespread lysosomal hypertrophy in the central nervous system was detected. This neuronal vacuolation was particularly severe in the lateral thalamic nuclei, medullary reticular nuclei, vestibular nuclei, inferior olivary complex, and deep cerebellar nuclei. The oldest animals (20 months old) displayed a clear neuronal loss and gliosis, particularly in those regions, where the most severe vacuolation was found. The severe ataxic gait of the older mice was likely due to the dramatic loss of Purkinje cells, intensive astrogliosis and vacuolation of neurons in the deep cerebellar nuclei, and the severe vacuolation of the cells in vestibular and cochlear nuclei. The impaired bladder function and subsequent hydronephrosis were secondary to involvement of the central nervous system. These findings demonstrate that the glycosylasparaginase-deficient mice share many neuropathological features with human AGU patients, providing a suitable animal model to test therapeutic strategies in the treatment of the central nervous system effects in AGU. 相似文献
5.
6.
Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus 总被引:13,自引:0,他引:13
Asumalahti K Veal C Laitinen T Suomela S Allen M Elomaa O Moser M de Cid R Ripatti S Vorechovsky I Marcusson JA Nakagawa H Lazaro C Estivill X Capon F Novelli G Saarialho-Kere U Barker J Trembath R Kere J;Psoriasis Consortium 《Human molecular genetics》2002,11(5):589-597
PSORS1, near HLA-C, is the major genetic determinant of psoriasis. We present genetic and structural evidence suggesting a major role for the HCR gene at the PSORS1 locus. Genotyping of 419 families from six populations revealed that coding single-nucleotide polymorphisms of HCR formed a conserved allele HCR*WWCC that associated highly significantly with psoriasis and with the HLA-Cw6 allele in all populations. Because of strong linkage disequilibrium between HLA-Cw6 and HCR*WWCC, the two genes could not be genetically distinguished by this sample size. However, the variant HCR allele was predicted to differ in secondary structure from the wild-type protein. HCR protein expression in lesional psoriatic skin differed considerably from that observed in normal skin. These results provide strong evidence for the HCR*WWCC allele as a major genetic determinant for psoriasis, probably by a mechanism impacting on keratinocyte proliferation. 相似文献
7.
Jenni Simonen Kati Kataja Henna Pirskanen Marja Holmila Christoffer Tigerstedt 《Addiction Research & Theory》2017,25(4):342-348
Background: Typically, research on parents’ and children’s interactions around alcohol issues focuses on how parenting styles and parents’ examples affect teenager’s drinking habits. In this paper, we approach the theme from the youngsters’ perspective. We ask how teenagers describe the interaction on alcohol-related issues with their parents and how they would like their parents to act during these interactions.Data and methods: The article applies the concept of trust, which is seen as a feature connecting all kinds of communities, and especially families. We pay attention to whether alcohol issues challenge trustful relations and give rise to contradictions and complications in the interactions between parents and children.Results: The analysis shows the ways how trust is maintained and challenged in teenagers? accounts of communication regarding alcohol with their parents. It also shows that although trust is tested in several ways, it is essential for teenagers. Even though teenagers tell how they can mislead their parents by using strategies that challenge trust, they nevertheless highlight the importance of trusting ties with parents. Teenagers do not exclude their parents from alcohol-related discussion but expect rules, communication and authority from them. Our data suggest that teenagers also want to protect their parents from disappointments caused by their own actions.Conclusions: A trusting parent–child relationship, based on dialog rather than opposition, seems to play a significant role in guiding teenagers’ alcohol-related attitudes and practices. 相似文献
8.
Kati Talvinen Henna Karra Reino Pitkänen Ilmari Ahonen Marjukka Nykänen Minnamaija Lintunen Mirva Söderström Teijo Kuopio Pauliina Kronqvist 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》2013,121(10):945-953
Cell cycle regulators cdc27 and securin participate in control of the mitotic checkpoint and survey the mitotic spindle to maintain chromosomal integrity. This is achieved by their functions in metaphase–anaphase transition, DNA damage repair, enhancement of mitotic arrest and apoptosis. We report on the roles of cdc27 and securin in aneuploidy and prognosis of breast cancer. The study comprises 429 breast cancer patients with up to 22 years of follow‐up. DNA content was determined by image cytometry, and immunopositivity for cdc27 and securin was based on tissue microarrays. An inverse association between cdc27 and securin expression was observed in both image cytometric and immunohistochemical analyses. Low cdc27 and high securin expression identified patients with significant difference in disease outcome. Cdc27 and securin immunoexpression identified patients at risk of early cancer death within five years from diagnosis. In multivariate analysis, the combination of cdc27 and securin immunohistochemistry was the strongest predictor of cancer death after lymph node status. We demonstrate, for the first time in human breast cancer, the prognostic value of cdc27 and securin immunohistochemistry. Cdc27 and securin appear promising biomarkers for applications in predicting disease progression, prognostication of individual patients and potential in anti‐mitotic drug development. 相似文献
9.
Pivi Vanttola Sampsa Puttonen Kati Karhula Tuula Oksanen Mikko Hrm 《Journal of sleep research》2020,29(3)
The prevalence of shift work disorder (SWD) has been studied using self‐reported data and the International Classification of Sleep Disorders, Second Edition (ICSD‐2) criteria. We examined the prevalence in relation to ICSD‐2 and ICSD‐3 criteria, work schedules and the number of non‐day shifts (work outside 06:00–18:00 hours) using objective working‐hours data. Secondly, we explored a minimum cut‐off for the occurrence of SWD symptoms. Hospital shift workers without (n = 1,813) and with night shifts (n = 2,917) and permanent night workers (n = 84) answered a survey (response rate 69%) on SWD and fatigue on days off. The prevalence of SWD was calculated for groups with ≥1, ≥3, ≥5 and ≥7 monthly non‐day shifts utilizing the working hours registry. ICSD‐3‐based SWD prevalence was 2.5%–3.7% (shift workers without nights), 2.6%–9.5% (shift workers with nights) and 6.0% (permanent night workers), depending on the cut‐off of non‐day shifts (≥7–1/month, respectively). The ICSD‐2‐based prevalence was higher: 7.1%–9.2%, 5.6%–33.5% and 16.7%, respectively. The prevalence was significantly higher among shift workers with than those without nights (p‐values <.001) when using the cut‐offs of ≥1–3 non‐day shifts. Shift workers with nights who had ≥3 days with ICSD‐3‐based SWD symptoms/month more commonly had fatigue on days off (49.3%) than those below the cut‐off (35.8%, p < .05). The ICSD‐3 criteria provided lower estimates for SWD prevalence than ISCD‐2 criteria, similarly to exclusion of employees with the fewest non‐day shifts. The results suggest that a plausible cut‐off for days with ICSD‐3‐based SWD symptoms is ≥3/month, resulting in 3%–6% prevalence of SWD. 相似文献
10.