Universal DNA methylation age across mammalian tissues.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

Human continuous glucose monitors for measurement of glucose in dairy cows.

If validated for use in dairy cattle, interstitial continuous glucose monitors (CGMs) could be easily implemented, informative tools for research, clinical, and perhaps even on-farm applications. To evaluate their efficacy, 2 experiments were conducted, during which lactating Holstein cows were fit with indwelling jugular catheters, as well as FreeStyle Libre (FSL; Abbott) and Dexcom G6 (DexCom Inc.) CGMs secured either behind their polls, lateral to their ears, or beneath their pin bones on their upper rear legs. During the first experiment, blood (measured with a handheld glucometer) and interstitial glucose measurements were collected from 13 cows every 4 h for 96 h. In the second experiment, the same measurements were collected from 8 cows every 15 min for 6 h. At the mid-point of the sampling period (3 h), cows received a bolus dose of dextrose to facilitate comparisons across a broad range of glucose concentrations. Results from both experiments determined that functional longevity of the sensors was greatest for those sensors secured near the ear. Likewise, interstitial measurements from the ear sensors were most closely correlated with blood glucose concentrations (r = 0.82 and r = 0.71 for FSL ear and Dexcom G6 ear, respectively). Unfortunately, accuracy calculated as absolute relative error was low, at 60.7% or less. As a result of the low accuracy, even though both ear sensors detected an increase in glucose concentrations following the bolus dose, neither produced results exactly matching blood glucose measurements. The results of this work indicate that the FSL and Dexcom G6 CGMs are not currently capable of replacing blood-based glucose measurements.

Comparison of production-related responses to hyperinsulinemia and hypoglycemia induced by clamp procedures or heat stress of lactating dairy cattle.

Hyperinsulinemia concurrent with hypoglycemia is one of a myriad of physiological changes typically experienced by lactating dairy cows exposed to heat stress, the consequences of which are not yet well defined or understood. Therefore, the objective of this experiment was to separate the production-related effects of hyperinsulinemia with hypoglycemia from those of a hyperthermic environment. Multiparous lactating Holstein cows (n = 23; 58 ± 4 d in milk, 3.1 ± 0.3 lactations) were housed in temperature-controlled rooms and all were subjected to 4 experimental periods as follows: (1) thermoneutral (TN; temperature-humidity index of 65.1 ± 0.2; d 1-5), (2) TN + hyperinsulinemic-hypoglycemic clamp (HHC; insulin infused at 0.3 µg/kg of BW per h, glucose infused to maintain 90 ± 10% of baseline blood glucose for 96 h; d 6-10), (3) heat stress (HS; temperature-humidity index of 72.5 ± 0.2; d 16-20), and (4) HS + euglycemic clamp (EC; glucose infused to reach 100 ± 10% of TN baseline blood glucose for 96 h; d 21-25). Cows were fed and milked twice daily. Feed refusals were collected once daily for calculation of daily dry matter intake, and milk samples were collected at the beginning and end of each period for component analyses. Circulating insulin concentrations were measured in daily blood samples, whereas glucose concentrations were measured more frequently and variably in association with clamp procedures. Rectal temperatures and respiration rates were greater during HS than TN, as expected, and states of hyperinsulinemia and hypoglycemia were successfully induced by the HHC and high ambient temperatures (HS and EC). Feed intake differed based upon thermal environment as it was similar during TN and HHC periods, and declined for HS and EC. Milk production was not entirely reflective of feed intake as it was greatest during TN, intermediate during HHC, and lowest during HS and EC. All milk components differed with the experimental period, primarily in response to the thermal environment. Interestingly, TN baseline glucose concentrations were highly correlated with the change in glucose from TN to HS, and were related to glycemic status during HS. Furthermore, although few in number, those cows that failed to become hypoglycemic during HS tended to have a greater reduction in milk yield. The work presented here addresses a critical knowledge gap by broadening our understanding of the physiological response to heat stress and the related changes in glycemic state. This broadened understanding is fundamental for the development of novel, innovative management strategies as the dairy industry is compelled to become increasingly efficient in spite of global warming.

The Distribution, Seasonal Abundance, and Environmental Factors Contributing to the Presence of the Asian Longhorned Tick (Haemaphysalis longicornis, Acari: Ixodidae) in Central Appalachian Virginia.

Over the past decade, Haemaphysalis longicornis, the Asian longhorned tick, has undergone a geographic range expansion in the United States, from its historical range in east Asia. This tick has been characterized by its frequent parasitism of livestock, an ability to reproduce through parthenogenesis, and its ability to transmit a variety of vector-borne pathogens to livestock, wildlife, and human hosts in its native geographic range. Thus far in the United States, 17 states have reported H. longicornis populations, including 38 counties in Virginia. These numbers come from presence-absence reports provided to the U.S. Department of Agriculture, but little has been reported about this ticks' seasonality in Virginia or its habitat preferences. Our current study detected H. longicornis populations in seven of the nine surveyed counties in Virginia. Haemaphysalis longicornis were observed in multiple habitat types including mixed hardwood forests and pastures, with abundant H. longicornis populations detected at one particular pasture site in Wythe County. This study also attempted to investigate environmental conditions that may be of importance in predicting tick presence likelihood. While sample size limited the scope of these efforts, habitat type and climatic metrics were found to be important indicators of H. longicornis collection success and abundance for both the nymphal and larval life stages. This current study reports useful surveillance data for monitoring these tick populations as they become established in the western half of Virginia and provides insight into their current distribution and maintenance over a large study region.

Long-term observations of cervical cancer.

A consecutive series of approximately 1100 patients, treated for cancer of the cervix over a span of 45 years, presents an increasingly favorable stage distribution. Emergence of exfoliative cytology as a diagnostic technique accelerates allocation of new patients to Stage I. Cumulative rates of dying from cervical cancer equate improved survival in terms of differences in prognosis and in effectiveness of treatment. Long-term observations bring into focus interval changes affecting the reservoir of individuals remaining at risk, which is maintained in accordance with rates of new patient inflow, as well as withdrawal for all categories of attrition. The several factors determining that balance, including age at diagnosis of cervical cancer, do not fall equally on all clinical stages. Age, a dominant factor determining incidence of second primary malignancies, may also have significance in unraveling the obscure etiology of corporeal malignancies evolving among patients irradiated in the treatment of cervical cancer.