Blocking cell cycle progression through CDK4/6 protects against chronic kidney disease

Acute and chronic kidney injuries induce increased cell cycle progression in renal tubules. While increased cell cycle progression promotes repair after acute injury, the role of ongoing tubular cell cycle progression in chronic kidney disease is unknown. Two weeks after initiation of chronic kidney disease, we blocked cell cycle progression at G1/S phase by using an FDA-approved, selective inhibitor of CDK4/6. Blocking CDK4/6 improved renal function and reduced tubular injury and fibrosis in 2 murine models of chronic kidney disease. However, selective deletion of cyclin D1, which complexes with CDK4/6 to promote cell cycle progression, paradoxically increased tubular injury. Expression quantitative trait loci (eQTLs) for CCND1 (cyclin D1) and the CDK4/6 inhibitor CDKN2B were associated with eGFR in genome-wide association studies. Consistent with the preclinical studies, reduced expression of CDKN2B correlated with lower eGFR values, and higher levels of CCND1 correlated with higher eGFR values. CDK4/6 inhibition promoted tubular cell survival, in part, through a STAT3/IL-1β pathway and was dependent upon on its effects on the cell cycle. Our data challenge the paradigm that tubular cell cycle progression is beneficial in the context of chronic kidney injury. Unlike the reparative role of cell cycle progression following acute kidney injury, these data suggest that blocking cell cycle progression by inhibiting CDK4/6, but not cyclin D1, protects against chronic kidney injury

Gene expression profiling of human whole blood samples with the Illumina WG-DASL assay

<p>Abstract</p> <p>Background</p> <p>Microarray-based gene expression analysis of peripheral whole blood is a common strategy in the development of clinically relevant biomarker panels for a variety of human diseases. However, the results of such an analysis are often plagued by decreased sensitivity and reliability due to the effects of relatively high levels of globin mRNA in whole blood. Globin reduction assays have been shown to overcome such effects, but they require large amounts of total RNA and may induce distinct gene expression profiles. The Illumina whole genome DASL assay can detect gene expression levels using partially degraded RNA samples and has the potential to detect rare transcripts present in highly heterogeneous whole blood samples without the need for globin reduction. We assessed the utility of the whole genome DASL assay in an analysis of peripheral whole blood gene expression profiles.</p> <p>Results</p> <p>We find that gene expression detection is significantly increased with the use of whole genome DASL compared to the standard IVT-based direct hybridization. Additionally, globin-probe negative whole genome DASL did not exhibit significant improvements over globin-probe positive whole genome DASL. Globin reduction further increases the detection sensitivity and reliability of both whole genome DASL and IVT-based direct hybridization with little effect on raw intensity correlations. Raw intensity correlations between total RNA and globin reduced RNA were 0.955 for IVT-based direct hybridization and 0.979 for whole genome DASL.</p> <p>Conclusions</p> <p>Overall, the detection sensitivity of the whole genome DASL assay is higher than the IVT-based direct hybridization assay, with or without globin reduction, and should be considered in conjunction with globin reduction methods for future blood-based gene expression studies.</p

The impact of life course exposures to neighbourhood deprivation on health and well-being: a review of the long-term neighbourhood effects literature

BACKGROUND:In this review article, we detail a small but growing literature in the field of health geography that uses longitudinal data to determine a life course component to the neighbourhood effects thesis. For too long, there has been reliance on cross-sectional data to test the hypothesis that where you live has an effect on your health and well-being over and above your individual circumstances. METHODS:We identified 53 articles that demonstrate how neighbourhood deprivation measured at least 15 years prior affects health and well-being later in life using the databases Scopus and Web of Science. RESULTS:We find a bias towards US studies, the most common being the Panel Study of Income Dynamics. Definition of neighbourhood and operationalization of neighbourhood deprivation across most of the included articles relied on data availability rather than a priori hypothesis. CONCLUSIONS:To further progress neighbourhood effects research, we suggest that more data linkage to longitudinal datasets is required beyond the narrow list identified in this review. The limited literature published to date suggests an accumulation of exposure to neighbourhood deprivation over the life course is damaging to later life health, which indicates improving neighbourhoods as early in life as possible would have the greatest public health improvement

Mimicry of Food Intake: The Dynamic Interplay between Eating Companions

Numerous studies have shown that people adjust their intake directly to that of their eating companions; they eat more when others eat more, and less when others inhibit intake. A potential explanation for this modeling effect is that both eating companions' food intake becomes synchronized through processes of behavioral mimicry. No study, however, has tested whether behavioral mimicry can partially account for this modeling effect. To capture behavioral mimicry, real-time observations of dyads of young females having an evening meal were conducted. It was assessed whether mimicry depended on the time of the interaction and on the person who took the bite. A total of 70 young female dyads took part in the study, from which the total number of bites (N = 3,888) was used as unit of analyses. For each dyad, the total number of bites and the exact time at which each person took a bite were coded. Behavioral mimicry was operationalized as a bite taken within a fixed 5-second interval after the other person had taken a bite, whereas non-mimicked bites were defined as bites taken outside the 5-second interval. It was found that both women mimicked each other's eating behavior. They were more likely to take a bite of their meal in congruence with their eating companion rather than eating at their own pace. This behavioral mimicry was found to be more prominent at the beginning than at the end of the interaction. This study suggests that behavioral mimicry may partially account for social modeling of food intake

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A Systematic Review of the Efficacy of Interventions that Aim to Increase Self-Compassion on Nutrition Habits, Eating Behaviours, Body Weight and Body Image

Overweight and obesity are universal health challenges, with behavioural weight management often failing to produce long-term effects. Various psychological factors, including body dissatisfaction and disordered eating, have been linked to weight gain overtimes. However, the majority of weight loss interventions do not address these aspects. Additionally, there has been a growing interest in the potential benefits of self-compassion as a new approach to promoting both physical and mental health. This systematic review investigated the effects of interventions that aim to increase self-compassion on obesity and weight-related psychological conditions. Four electronic databases were searched using terms adapted from previous systematic reviews on nutrition and body weight, self-compassion, eating disorders and body image. This review was conducted using the PRISMA guidelines for systematic reviewers. The search identified six studies that met eligible criteria for the review. Results indicate that self-compassion can be beneficial for weight loss, nutrition behaviours, eating behaviours and body image. However, the number of studies is limited, and most of the studies have serious limitations. Further research using robust methodologies is needed to determine the efficacy of self-compassion on body weight and related behaviours