Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a)

Cellular senescence can be triggered by telomere shortening as well as a variety of stresses and signaling imbalances. We used multiparameter single-cell detection methods to investigate upstream signaling pathways and ensuing cell cycle checkpoint responses in human fibroblasts. Telomeric foci containing multiple DNA damage response factors were assembled in a subset of senescent cells and signaled through ATM to p53, upregulating p21 and causing G1 phase arrest. Inhibition of ATM expression or activity resulted in cell cycle reentry, indicating that stable arrest requires continuous signaling. ATR kinase appears to play a minor role in normal cells but in the absence of ATM elicited a delayed G2 phase arrest. These pathways do not affect expression of p16, which was upregulated in a telomere- and DNA damage-independent manner in a subset of cells. Distinct senescence programs can thus progress in parallel, resulting in mosaic cultures as well as individual cells responding to multiple signals.     

Adequate but not supplemental folic acid combined with soy isoflavones during early life improves bone health at adulthood in male mice

Previous investigations from our laboratory have demonstrated that neonatal exposure to soy isoflavones (ISO) improves bone outcomes in CD-1 mice at adulthood with greater benefits in females than males. This study determined whether early-life exposure to supplemental folic acid (FA) — that may enhance DNA methylation of target genes — in combination with ISO provides greater benefits to male bone development than ISO alone. CD-1 dams were randomized to a low (0 mg/kg diet), adequate (2 mg/kg diet) or supplemental (8 mg/kg diet) level of FA during pregnancy and lactation. Offspring received corn oil or ISO (7 mg/kg of body weight per day) from postnatal day 1–10. From weaning, males were fed adequate FA and studied to age 4 months. Offspring exposed to adequate FA+ISO had multiple benefits to bone health: higher (P<.05) bone mineral density (BMD) and greater (P<.05) resistance to fracture at the femur and lumbar spine than mice exposed to adequate FA alone. Exposure to supplemental FA+ISO resulted in higher (P<.05) serum osteoprotegerin (OPG), and a higher ratio of OPG to receptor activator for nuclear factor κβ ligand (RANKL) but did not result in greater BMD or strength at the femur or lumbar spine than supplemental FA alone. In conclusion, early-life exposure to adequate FA+ISO provided functional benefits to male bone development, while improvements induced by supplemental FA+ISO were limited to a higher level of serum OPG. Mechanistic studies are needed to better understand how FA and ISO improve bone development in male offspring.     

Angiogenic Properties of Human Dental Pulp Stem Cells

Angiogenesis, the formation of capillaries from pre-existing blood vessels, is a key process in tissue engineering. If blood supply cannot be established rapidly, there is insufficient oxygen and nutrient transport and necrosis of the implanted tissue will occur. Recent studies indicate that the human dental pulp contains precursor cells, named dental pulp stem cells (hDPSC) that show self-renewal and multilineage differentiation capacity. Since these cells can be easily isolated, cultured and cryopreserved, they represent an attractive stem cell source for tissue engineering. Until now, only little is known about the angiogenic abilities and mechanisms of the hDPSC. In this study, the angiogenic profile of both cell lysates and conditioned medium of hDPSC was determined by means of an antibody array. Numerous pro-and anti-angiogenic factors such as vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1) and endostatin were found both at the mRNA and protein level. hDPSC had no influence on the proliferation of the human microvascular endothelial cells (HMEC-1), but were able to significantly induce HMEC-1 migration in vitro. Addition of the PI3K-inhibitor {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 and the MEK-inhibitor U0126 to the HMEC-1 inhibited this effect, suggesting that both Akt and ERK pathways are involved in hDPSC-mediated HMEC-1 migration. Antibodies against VEGF also abolished the chemotactic actions of hDPSC. Furthermore, in the chicken chorioallantoic membrane (CAM) assay, hDPSC were able to significantly induce blood vessel formation. In conclusion, hDPSC have the ability to induce angiogenesis, meaning that this stem cell population has a great clinical potential, not only for tissue engineering but also for the treatment of chronic wounds, stroke and myocardial infarctions.     

Canadians’ Perceptions of Food,Diet, and Health – A National Survey

Background

Poor nutrition is harmful to one’s health as it can lead to overweight and obesity and a number of chronic diseases. Understanding consumer perceptions toward diet and nutrition is critical to advancing nutrition-related population health interventions to address such issues. The purpose of this paper was to examine Canadians’ perceived health and diet status, compared to their actual health status, and general concern about their own diet and beliefs about health. Also analyzed were some of the perceived barriers to eating “healthy” foods, with a focus on the availability of “healthy” processed foods.

Methods

Two surveys were administered online to a group of Canadian panelists from all ten provinces during May 2010 to January 2011. Thirty thousand were invited; 6,665 completed the baseline survey and 5,494 completed the second survey. Panelists were selected to be nationally representative of the Canadian adult population by age, sex, province and education level, according to 2006 census data.

Results

Approximately one third of Canadians perceived their health or diet to be very good while very few Canadians perceived their health or diet to be very poor. While the majority of Canadians believed food and nutrition to be very important for improving one’s health, fewer Canadians were concerned about their own diets. The majority of Canadians reported difficulty finding “healthy” processed foods (low in salt and sugar and with sufficient vitamins and minerals). Many also reported difficulty finding healthy foods that are affordable.

Conclusion

Although consumers believe that nutrition is one of the most important factors for maintaining health, there are still a number of attitudinal and perceived environmental barriers to healthy eating.     

Clinical Impact of the Temporal Relationship between Depression and Type 2 Diabetes: The Fremantle Diabetes Study Phase II

Background

The clinical features of type 2 diabetes may differ depending on whether first depression episode precedes or follows the diagnosis of diabetes.

Methods

Type 2 patients from the observational community-based Fremantle Diabetes Study Phase II underwent assessment of lifetime depression using the Brief Lifetime Depression Scale (developed and validated for this study) supplemented by information on current depression symptoms (Patient Health Questionnaire, 9-item version) and use of antidepressants. Patients were categorized as never depressed (Group 1), having had depression before diabetes diagnosis (Group 2), diagnosed with depression and diabetes within 2 years of each other (Group 3) and having depression after diabetes diagnosis (Group 4).

Results

Of 1391 patients, 20.8% were assigned to Group 2, 6.0% to Group 3 and 14.5% to Group 4. In Group 2, depression occurred a median 15.6 years before diabetes onset at age 37.2±14.7 years. These patients had similar clinical characteristics to never depressed patients except for reduced self-care behaviours and having more symptomatic peripheral arterial disease. In Group 4, depression occurred a median 9.9 years after diabetes onset at age 59.8±13.0 years. These patients had long duration diabetes, poor glycaemic control, more intensive management and more diabetic complications. Group 4 patients had more current depression than Group 2 but were less likely to be receiving antidepressants.

Conclusions/Interpretation

The clinical features of depression and type 2 diabetes are heterogeneous depending on their temporal relationship. There may be corresponding differences in the pathogenesis of depression in diabetes that have implications for diagnosis and management.     

Effects of increased meal frequency on fat oxidation and perceived hunger

Objective:

Consuming smaller, more frequent meals is often advocated as a means of controlling body weight, but studies demonstrating a mechanistic effect of this practice on factors associated with body weight regulation are lacking. The purpose of this study was to compare the effect of consuming three (3M) vs. six meals (6M) per day on 24‐h fat oxidation and subjective ratings of hunger.

Design and Methods:

Lean (body mass index <25 kg/m²) subjects (7M, 8F) were studied in a whole‐room calorimeter on two occasions in a randomized cross‐over design. Subjects were provided isoenergetic, energy balanced diets with a 1‐ to 2‐week washout between conditions. Hunger, fullness, and “desire to eat” ratings were assessed throughout the day using visual analog scales and quantified as area under the curve (AUC).

Results:

There were no differences (P < 0.05) in 24‐h energy expenditure (8.7 ± 0.3 vs. 8.6 ± 0.3 mj d^?1), 24‐h respiratory quotient (0.85 ± 0.01 vs. 0.85 ± 0.01), or 24‐h fat oxidation (82 ± 6 vs. 80 ± 7 g day^‐1) between 3M and 6M, respectively. There was no difference in fullness 24‐h AUC, but hunger AUC (41850 ± 2255 vs. 36612 ± 2556 mm.24 h, P = 0.03) and “desire to eat” AUC (47061 ± 1791 vs. 41170 ± 2574 mm.24 h, P = 0.03) were greater during 6M than 3M.

Conclusion:

We conclude that increasing meal frequency from three to six per day has no significant effect on 24‐h fat oxidation, but may increase hunger and the desire to eat.

     

Environmental,geographical and time-related impacts on avian malaria infections in native and introduced populations of house sparrows (Passer domesticus), a globally invasive species

Aim

The increasing spread of vector-borne diseases has resulted in severe health concerns for humans, domestic animals and wildlife, with changes in land use and the introduction of invasive species being among the main possible causes for this increase. We explored several ecological drivers potentially affecting the local prevalence and richness of avian malaria parasite lineages in native and introduced house sparrows (Passer domesticus) populations.

Location

Global.

Time period

2002–2019.

Major taxa studied

Avian Plasmodium parasites in house sparrows.

Methods

We analysed data from 2,220 samples from 69 localities across all continents, except Antarctica. The influence of environment (urbanization index and human density), geography (altitude, latitude, hemisphere) and time (bird breeding season and years since introduction) were analysed using generalized additive mixed models (GAMMs) and random forests.

Results

Overall, 670 sparrows (30.2%) were infected with 22 Plasmodium lineages. In native populations, parasite prevalence was positively related to urbanization index, with the highest prevalence values in areas with intermediate urbanization levels. Likewise, in introduced populations, prevalence was positively associated with urbanization index; however, higher infection occurred in areas with either extreme high or low levels of urbanization. In introduced populations, the number of parasite lineages increased with altitude and with the years elapsed since the establishment of sparrows in a new locality. Here, after a decline in the number of parasite lineages in the first 30 years, an increase from 40 years onwards was detected.

Main conclusions

Urbanization was related to parasite prevalence in both native and introduced bird populations. In invaded areas, altitude and time since bird introduction were related to the number of Plasmodium lineages found to be infecting sparrows.