Aging is a main risk factor for osteoarthritis (OA). FoxO transcription factors protect against cellular and organismal aging, and FoxO expression in cartilage is reduced with aging and in OA. To investigate the role of FoxO in cartilage, Col2Cre-FoxO1, 3, and 4 single knockout (KO) and triple KO mice (Col2Cre-TKO) were analyzed. Articular cartilage in Col2Cre-TKO and Col2Cre-FoxO1 KO mice was thicker than in control mice at 1 or 2 months of age. This was associated with increased proliferation of chondrocytes of Col2Cre-TKO mice in vivo and in vitro. OA-like changes developed in cartilage, synovium, and subchondral bone between 4 and 6 months of age in Col2Cre-TKO and Col2Cre-FoxO1 KO mice. Col2Cre-FoxO3 and FoxO4 KO mice showed no cartilage abnormalities until 18 months of age when Col2Cre-FoxO3 KO mice had more severe OA than control mice. Autophagy and antioxidant defense genes were reduced in Col2Cre-TKO mice. Deletion of FoxO1/3/4 in mature mice using Aggrecan(Acan)-CreERT2 (AcanCreERT-TKO) also led to spontaneous cartilage degradation and increased OA severity in a surgical model or treadmill running. The superficial zone of knee articular cartilage of Col2Cre-TKO and AcanCreERT-TKO mice exhibited reduced cell density and markedly decreased In vitro, ectopic FoxO1 expression increased and synergized with transforming growth factor-β stimulation. In OA chondrocytes, overexpression of FoxO1 reduced inflammatory mediators and cartilage-degrading enzymes, increased protective genes, and antagonized interleukin-1β effects. Our observations suggest that FoxO play a key role in postnatal cartilage development, maturation, and homeostasis and protect against OA-associated cartilage damage.

Diarrhea remains one of the main sources of morbidity and mortality in the world, and a large proportion is caused by diarrheagenic Escherichia coli. In Mongolia, the epidemiology of diarrheagenic E. coli has not been well studied. A total of 238 E. coli strains from children with sporadic diarrhea and 278 E. coli strains from healthy children were examined by PCR for 10 virulence genes: enteropathogenic E. coli (EPEC) eae, tir, and bfpA; enterotoxigenic E. coli (ETEC) lt and st; enteroinvasive E. coli (EIEC) ipaH; enterohemorragic E. coli stx1 and stx2; and enteroaggregative E. coli (EAEC) aggR and astA. EAEC strains without AggR were identified by the HEp-2 cell adherence test. The detection of EAEC, ETEC, EPEC, and EIEC was significantly associated with diarrhea. The incidence of EAEC (15.1%), defined by either a molecular or a phenotypic assay, was higher in the diarrheal group than any other category (0 to 6.0%). The incidence of AggR-positive EAEC in the diarrheal group was significantly higher than in the control group (8.0 versus 1.4%; P ‫؍‬ 0.0004), while that of AggR-negative EAEC was not (7.1 versus 4.3%). Nineteen AggR-positive EAEC strains harbored other EAEC virulence genes-aggA, 2 (5.5%); aafA, 4 (11.1%); agg-3a, 5 (13.8%); aap, 8 (22.2%); aatA, 11 (30.5%); capU, 9 (25.0%); pet, 6 (16.6%); and set, 3 (8.3%)-and showed 15 genotypes. EAEC may be an important pathogen of sporadic diarrhea in Mongolian children. Genetic analysis showed the heterogeneity of EAEC but illustrated the importance of the AggR regulon (denoting typical EAEC) as a marker for virulent EAEC strains.Diarrhea continues to be one of the most common causes of morbidity and mortality among infants and children in developing countries (5, 18). Five distinct classes of diarrheagenic Escherichia coli (DEC) are recognized as being associated with diarrheal disease. They are enterotoxigenic E. coli (ETEC), enteroinvasive E. coli (EIEC), enteropathogenic E. coli (EPEC), enterohemorrhagic E. coli (EHEC), and enteroaggregative E. coli (EAEC); diffuse adhering E. coli (DAEC) may represent a sixth category, but this has not been clearly established (18). Each class of DEC is defined on the basis of distinct virulence characteristics, and tests for these characteristics have been developed to distinguish DEC classes from each other and from nonpathogenic E. coli strains of the normal flora (15, 34). The epidemiological significance of each E. coli category in childhood diarrhea varies with the geographical area. It has become clear that there are important regional differences in the prevalences of the different categories of DEC. The incidences of diarrheal illnesses caused by the different categories of DEC were examined mainly in Latin America, Africa, southern and Southeast Asia, and the Middle East (1,3,25,32,35,36,45). Study of the prevalences of DEC categories and their importance in childhood diarrhea has not been carried out in Mongolia. Therefore, to define the association of various categories of E. coli with diarrhea in Mongolia, w...

In order to evaluate the protective role of the maternal antibody against mother-to-child transmission of HTLV-I, we followed a total of 780 children born to HTLV-I carrier mothers by investigating the level of anti-HTLV-I antibody transferred in utero, decline of the maternal antibody and seroconversion in post-natal life. The anti-HTLV-I antibody was positively detected within the first 3-6 months of life and declined at 6-12 months after birth in all children. After the maternal antibody declined, seroconversion occurred in some of the children following either breast feeding or bottle feeding. The seroconversion rates of short-term (less than or equal to 6 months) and long-term (greater than or equal to 7 months) breast feeders were 4.4% (4/90 cases) and 14.4% (20/139 cases), and the rate of bottle feeders was 5.7% (9/158 cases). Long-term breast feeding yielded more seroconverters than short-term breast feeding; 14.4% (20/139 cases) vs. 4.4% (4/90 cases), RR = 3.68, p = 0.018. The seroconversion rate of short-term breast feeders was nearly equal to that of bottle feeders; 4.4% (4/90 cases) vs. 5.7% (9/158 cases), RR = 0.770, p = 0.471. When neonatal lymphocytes were cultured with breast milk cells of HTLV-I carrier mothers, the in vitro infection of HTLV-I was inhibited by the addition of HTLV-I-seropositive cord-blood plasma. Our results suggest that the maternal antibody may inhibit HTLV-I infection by short-term breast feeding but not by long-term breast feeding after decline of the maternal antibody.

The WW domain-containing protein 2 ( Wwp2 ) gene, the host gene of miR-140, codes for the Wwp2 protein, which is an HECT-type E3 ubiquitin ligases abundantly expressed in articular cartilage. However, its function remains unclear. Here, we show that mice lacking Wwp2 and mice in which the Wwp2 E3 enzyme is inactivated (Wwp2-C838A) exhibit aggravated spontaneous and surgically induced osteoarthritis (OA). Consistent with this phenotype, WWP2 expression level is downregulated in human OA cartilage. We also identify Runx2 as a Wwp2 substrate and Adamts5 as a target gene, as similar as miR-140. Analysis of Wwp2-C838A mice shows that loss of Wwp2 E3 ligase activity results in upregulation of Runx2-Adamts5 signaling in articular cartilage. Furthermore, in vitro transcribed Wwp2 mRNA injection into mouse joints reduces the severity of experimental OA. We propose that Wwp2 has a role in protecting cartilage from OA by suppressing Runx2-induced Adamts5 via Runx2 poly-ubiquitination and degradation.

Intervertebral disk (IVD) degeneration is a prevalent age‐associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age‐related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO‐deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration.