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Altered transcriptional and epigenetic regulation of brain cell types may contribute to cognitive changes with advanced age. Using single-nucleus multi-omic DNA methylation and transcriptome sequencing (snmCT-seq) in frontal cortex from young adult and aged donors, we found widespread age- and sex-related variation in specific neuron types. The proportion of inhibitory SST- and VIP-expressing neurons was reduced in aged donors. Excitatory neurons had more profound age-related changes in their gene expression and DNA methylation than inhibitory cells. Hundreds of genes involved in synaptic activity, including EGR1, were less expressed in aged adults. Genes located in subtelomeric regions increased their expression with age and correlated with reduced telomere length. We further mapped cell-type-specific sex differences in gene expression and X-inactivation escape genes. Multi-omic single-nucleus epigenomes and transcriptomes provide new insight into the effects of age and sex on human neurons.

Abstract Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) of human post mortem brain in four differentially affected regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from donors with HD and age/sex matched controls, we found heterogeneity of glia which is altered in HD. We describe prominent changes in the abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight possible mechanisms that characterise the glial contribution to HD pathology including depletion of myelinating oligodendrocytes, an oligodendrocyte-specific upregulation of the calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1 A (PDE1A) and an upregulation of molecular chaperones as a cross-glial signature and a potential adaptive response to the accumulation of mutant huntingtin (mHTT). Our results support the hypothesis that glia have an important role in the pathology of HD, and show that all types of glia are affected in the disease.

Abstract The myelinated white matter tracts of the central nervous system (CNS) are essential for fast transmission of electrical impulses and are often differentially affected in human neurodegenerative diseases across CNS region, age and sex. We hypothesize that this selective vulnerability is underpinned by physiological variation in white matter glia. Using single nucleus RNA sequencing of human post-mortem white matter samples from the brain, cerebellum and spinal cord and subsequent tissue-based validation we found substantial glial heterogeneity with tissue region: we identified region-specific oligodendrocyte precursor cells (OPCs) that retain developmental origin markers into adulthood, distinguishing them from mouse OPCs. Region-specific OPCs give rise to similar oligodendrocyte populations, however spinal cord oligodendrocytes exhibit markers such as SKAP2 which are associated with increased myelin production and we found a spinal cord selective population particularly equipped for producing long and thick myelin sheaths based on the expression of genes/proteins such as HCN2. Spinal cord microglia exhibit a more activated phenotype compared to brain microglia, suggesting that the spinal cord is a more pro-inflammatory environment, a difference that intensifies with age. Astrocyte gene expression correlates strongly with CNS region, however, astrocytes do not show a more activated state with region or age. Across all glia, sex differences are subtle but the consistent increased expression of protein-folding genes in male donors hints at pathways that may contribute to sex differences in disease susceptibility. These findings are essential to consider for understanding selective CNS pathologies and developing tailored therapeutic strategies.

Despite the increasing prevalence of social media usage, the activity of dermatology journals and professional and patient-centered organizations on top social media platforms has not been investigated since 2012. We investigated a total of 124 dermatology journals, 242 professional organizations, and 78 patient-centered organizations to assess their presence and popularity on social media. Searches were conducted to identify journals and organizations on Facebook and Twitter. Similar searches were done for organizations on LinkedIn. The number of Facebook likes, Twitter followers, and LinkedIn followers of the dermatological entities were quantified. There were 22 (17.7%) dermatology journals active on Facebook and 21 (16.9%) on Twitter. Amongst the professional organizations, 114 (47.1%) were on Facebook, 69 (28.5%) on Twitter, and 50 (20.7%) on LinkedIn. In comparison, 68 (87.2%) patient-centered organizations were on Facebook, 56 (71.8%) on Twitter, and 56 (71.8%) on LinkedIn. Our results demonstrate that the popularity of dermatology journals and professional and patient-centered organizations on top social networking sites has grown markedly since 2012. Although the number of dermatology journals on social media has increased since 2012, their presence continues to trail behind professional and patient-centered dermatological organizations, suggesting underutilization of a valuable resource.

Abstract Telomere length is predictive of adult health and survival across vertebrate species. However, we currently do not know whether such associations result from among-individual differences in telomere length determined genetically or by early-life environmental conditions, or from differences in the rate of telomere attrition over the course of life that might be affected by environmental conditions. Here, we measured relative leukocyte telomere length (RLTL) multiple times across the entire lifespan of dairy cattle in a research population that is closely monitored for health and milk production and where individuals are predominantly culled in response to health issues. Animals varied in their change in RLTL between subsequent measurements and RLTL shortened more during early life and following hotter summers which are known to cause heat stress in dairy cows. The average amount of telomere attrition calculated over multiple repeat samples of individuals predicted a shorter productive lifespan, suggesting a link between telomere loss and health. TL attrition was a better predictor of when an animal was culled than their average TL or the previously for this population reported significant TL at the age of 1 year. Our present results support the hypothesis that TL is a flexible trait that is affected by environmental factors and that telomere attrition is linked to animal health and survival traits. Change in telomere length may represent a useful biomarker in animal welfare studies.

Health and survival are key goals for selective breeding in farm animals. Progress, however, is often limited by the low heritability of these animal fitness traits in addition to measurement difficulties. In this respect, relevant early-life biomarkers may be useful for breeding purposes. Telomere length (TL), measured in leukocytes, is a good candidate biomarker since TL has been associated with health, ageing, and stress in humans and other species. However, telomere studies are very limited in farm animals. Here, we examined the genetic background, genomic architecture, and factors affecting bovine TL measurements in early life, and the association of the latter with animal fitness traits expressed later in life associated with survival, longevity, health, and reproduction. We studied two TL measurements, one at birth (TLB) and another during the first lactation (TLFL) of a cow. We performed a genome-wide association study of dairy cattle TL, the first in a non-human species, and found that TLB and TLFL are complex, polygenic, moderately heritable, and highly correlated traits. However, genomic associations with distinct chromosomal regions were identified for the two traits suggesting that their genomic architecture is not identical. This is reflected in changes in TL throughout an individual’s life. TLB had a significant association with survival, length of productive life and future health status of the animal, and could be potentially used as an early-life biomarker for disease predisposition and longevity in dairy cattle.

The qPCR method provides an inexpensive, rapid method for estimating relative telomere length across a set of biological samples. Like all laboratory methods, it involves some degree of measurement error. The estimation of relative telomere length is done subjecting the actual measurements made (the Cq values for telomere and a control gene) to non-linear transformations and combining them into a ratio (the TS ratio). Here, we use computer simulations, supported by mathematical analysis, to explore how errors in measurement affect qPCR estimates of relative telomere length, both in cross-sectional and longitudinal data. We show that errors introduced at the level of Cq values are magnified when the TS ratio is calculated. If the errors at the Cq level are normally distributed and independent of true telomere length, those in the TS ratio are positively skewed and proportional to true telomere length. The repeatability of the TS ratio declines sharply with increasing error in measurement of the Cq values for telomere and/or control gene. In simulated longitudinal data, measurement error alone can produce a pattern of low correlation between successive measures of relative telomere length, coupled with a strong negative dependency of the rate of change on initial relative telomere length. Our results illustrate the importance of reducing measurement error: a small increase in error in Cq values can have large consequences for the power and interpretability of qPCR estimates of relative telomere length. The findings also illustrate the importance of characterising the measurement error in each dataset-coefficients of variation are generally unhelpful, and researchers should report standard deviations of Cq values and/or repeatabilities of TS ratios-and allowing for the known effects of measurement error when interpreting patterns of TS ratio change over time.

Telomeres cap the ends of linear chromosomes and shorten with age in many organisms. In humans short telomeres have been linked to morbidity and mortality. With the accumulation of longitudinal datasets the focus shifts from investigating telomere length (TL) to exploring TL change within individuals over time. Some studies indicate that the speed of telomere attrition is predictive of future disease. The objectives of the present study were to 1) characterize the change in bovine relative leukocyte TL (RLTL) across the lifetime in Holstein Friesian dairy cattle, 2) estimate genetic parameters of RLTL over time and 3) investigate the association of differences in individual RLTL profiles with productive lifespan. RLTL measurements were analysed using Legendre polynomials in a random regression model to describe TL profiles and genetic variance over age. The analyses were based on 1,328 repeated RLTL measurements of 308 female Holstein Friesian dairy cattle. A quadratic Legendre polynomial was fitted to the fixed effect of age in months and to the random effect of the animal identity. Changes in RLTL, heritability and within-trait genetic correlation along the age trajectory were calculated and illustrated. At a population level, the relationship between RLTL and age was described by a positive quadratic function. Individuals varied significantly regarding the direction and amount of RLTL change over life. The heritability of RLTL ranged from 0.36 to 0.47 (SE = 0.05-0.08) and remained statistically unchanged over time. The genetic correlation of RLTL at birth with measurements later in life decreased with the time interval between samplings from near unity to 0.69, indicating that TL later in life might be regulated by different genes than TL early in life. Even though animals differed in their RLTL profiles significantly, those differences were not correlated with productive lifespan (p = 0.954).

Telomere length (TL) is increasingly being used as a biomarker in epidemiological, biomedical and ecological studies. A wide range of DNA extraction techniques have been used in telomere experiments and recent quantitative PCR (qPCR) based studies suggest that the choice of DNA extraction method may influence average relative TL (RTL) measurements. Such extraction method effects may limit the use of historically collected DNA samples extracted with different methods. However, if extraction method effects are systematic an extraction method specific (MS) calibrator might be able to correct for them, because systematic effects would influence the calibrator sample in the same way as all other samples. In the present study we tested whether leukocyte RTL in blood samples from Holstein Friesian cattle and Soay sheep measured by qPCR was influenced by DNA extraction method and whether MS calibration could account for any observed differences. We compared two silica membrane-based DNA extraction kits and a salting out method. All extraction methods were optimized to yield enough high quality DNA for TL measurement. In both species we found that silica membrane-based DNA extraction methods produced shorter RTL measurements than the non-membrane-based method when calibrated against an identical calibrator. However, these differences were not statistically detectable when a MS calibrator was used to calculate RTL. This approach produced RTL measurements that were highly correlated across extraction methods (r > 0.76) and had coefficients of variation lower than 10% across plates of identical samples extracted by different methods. Our results are consistent with previous findings that popular membrane-based DNA extraction methods may lead to shorter RTL measurements than non-membrane-based methods. However, we also demonstrate that these differences can be accounted for by using an extraction method-specific calibrator, offering researchers a simple means of accounting for differences in RTL measurements from samples extracted by different DNA extraction methods within a study.

The physical, thermal, and chemical behavior of pulverized coal particles during thermal decomposition are examined for five coal types and two particle sizes for one of the bituminous coals. Particles were injected axially into a lean (35% excess air) methane/air flat flame with a nominal peak temperature of 1750°K. The significant events observed are classified by three time scales. Particles heat to the gas temperature in less than 10 msec, devolatilization occurs between 10 and 75 msec and, under the appropriate conditions, large soot particles are formed WRS and grow for times exceeding 75 msec. The events that accompany devolatilization are dependent upon coal type and particle size. For large bituminous particles (ca., 80 μm) a significant volatile fraction is ejected from the particle as a jet. This volatile jet reacts close to the particle producing a trail of small solid particles. The local heat released during the reaction of the volatiles, in combination with heterogeneous oxidation, increases the particle, temperature and raises it above that of the bulk gas stream. At later times, large soot structures, are formed which are attributed to the agglomeration of small, homogeneously formed soot on the volatile trail structures. Small bituminous particles (ca., 40 μm) burn with a higher intensity (i.e., higher temperature and more rapidly) with few trails and do not produce soot structures probably because of the more diffuse nature of the devolatilization process. Other ranks of coal exhibit different physical, thermal, and chemical behavior. For example, neither the lignites nor the anthracite produce volatile trials. Further, the particle temperature for the lignites is only slightly shifted above the bulk gas temperature in the devolatilization region while anthracite takes 50 msec to reach the bulk gas temperature level. This is attributable to the relatively low heat content of the volatiles in the former case and the low volatile content in the latter. The impact of the above observations on the formation of fuel NO is discussed. © 1981 Combustion Institute.

A thermal decomposition reactor is used to simulate the environment of a practical coal burner and assess the influence of fuel properties on the chemical behaviour that accompanies the thermal decomposition of pulverized coal particles. The present study complements and extends previous work that explored the physical and thermal behaviour. The rate of component burnout is determined for hydrogen, nitrogen and carbon as well as the evolution of NO and HCN, and the efficiency of fuel nitrogen conversion. The results demonstrate a significant dependency on coal particle size and coal type. Modelling demonstrates that the penetration of oxygen into the fuel-rich devolatilization cloud depends on particle size and coal properties and, as a result, controls to a large extent the evolution and transformation of the chemical constituents associated with the parent fuel. © 1988.

Incineration is a promising technique for the disposal of organic hazardous wastes. However, the waste destruction characteristics of turbulent spray flames have not been characterized. In the present research two reactors are used to simulate various aspects of liquid injection incinerator flame zones. The following questions are addressed: (1) Under what conditions do flames quantitatively destroy waste compounds, and (2) how must the flame be perturbed to cause it to fail to quantitatively destroy wastes. The two reactors operated on a simulated waste stream consisting of acrylonitrile, benzene, chlorobenzene, and chloroform. A microspray reactor was used to investigate destruction processes associated with individual droplets of waste compounds. A turbulent flame reactor used a heptane-fueled waste-doped turbulent spray flame to simulate incinerator flame-zone processes. The flames were found to be capable of quantitative waste destruction without the necessity of using common post-flame processes such as afterburners. Furthermore, the high waste destruction efficiency conditions corresponded to high combustion efficiency conditions (i.e., minimum CO and hydrocarbon emissions). Failure to achieve high destruction efficiency resulted from the perturbation of flame parameters. Failure conditions were identified with high and low theoretical air, low temperature, poor atomization quality, and flame impingement on a cold surface. Each failure condition also resulted in elevated CO and hydrocarbon emissions. Thus, the results suggest that CO and hydrocarbon measurements can be used as an indirect, continuous means of monitoring incinerator flame-zone performance. © 1985 Combustion Institute.

The correlation between atomization quality and the destruction efficiency of hazardous organic compounds was studied in a turbulent spray flame. The atomization quality was varied by both changing spray nozzle parameters and by inducing disruptive droplet combustion (secondary atomization) within the flame. The primary atomization quality was characterized by laser diagnotic size distribution measurements. The secondary atomization quality was determined from observations of disruptive atomization intensity on a train of monodisperse droplets within a high-temperature laminar reactor. For the primary atomization work, No. 2 fuel oil was doped with four target hazardous organic compounds (acrylonitrile, chloroform, benzene, and monochlorobenzene). The destruction efficiency of these compounds was measured under correct atomizer operating parameters and under off-design conditions in which the spray quality was degraded. The degraded spray quality conditions resulted in decreased destruction efficiency of the waste, and increased combustion intermediate emissions (carbon monoxide and total hydrocarbons). Comparison of measured droplet size distributions with performance showed that destruction efficiency was more closely correlated with the large droplet wing of the dropsize distribution than with the mean droplet size. A droplet evaporation/ trajectory model showed that the appearance of the target compounds in the exhaust corresponded with the fraction of the droplets that passed through the primary reaction zone unevaporated. The distruptive droplet combustion results showed that hazardous waste compounds are capable of inducing secondary atomization. Testing of benzal chloride (which did not cause the turbulent flame reactor showed that the occurrence of disruptive combustion correlated with increased target compound destruction efficiency and reduced combustion intermediate emissions. Thus, the results suggest that the presence of certain compounds or additives in waste streams may assist in obtaining improved performance when primary atomization is poor, as it is for slurry or sludge waste streams. © 1988 Combustion Institute.

This paper reports on the observed behavior of coal particles during thermal decomposition. The data presented are the first from a study initiated to address both the physical and chemical behavior of pulverized coal from the time of initial heating through the evolution of soot particulate. In the present study, pulverized (high volatile bituminous) coal was injected through a slit centered in a methaneair flat flame burner, and high resolution holography was employed to record the evolution of volatiles and the structure of soot particulate. Volatiles were observed to evolve in a variety of shapes that range from individual jets to uniformly distributed clouds. Coal particle fragments and/or incipient soot nodules (∼ 3 micron) were found to be present within the volatile gases during the evolution. Further from the burner, stringlike soot particles approaching 1600 microns in length were observed. © 1981.

The article discusses the Arcadia Programme at the Cambridge University in Cambridge, England aimed at creating a new and innovative curriculum to teach information literacy in higher education. It mentions that to ensure that the curriculum of the Programme is based on relevant and current research, a wide-ranging review of published materials and a modified Delphi study were conducted. It adds that a vision of information literacy is necessary for the new curriculum of the Programme.