Connexins and Diabetes

Cell-to-cell interactions via gap junctional communication and connexon hemichannels are involved in the pathogenesis of diabetes. Gap junctions are highly specialized transmembrane structures that are formed by connexon hemichannels, which are further assembled from proteins called “connexins.” In this paper, we discuss current knowledge about connexins in diabetes. We also discuss mechanisms of connexin influence and the role of individual connexins in various tissues and how these are affected in diabetes. Connexins may be a future target by both genetic and pharmacological approaches to develop treatments for the treatment of diabetes and its complications

Population based time trends and socioeconomic variation in use of radiotherapy and radical surgery for prostate cancer in a UK region: continuous survey

Objective To examine variation in the management of prostate cancer in patients with different socioeconomic status

Inbreeding depression across the lifespan in a wild mammal population

Inbreeding depression is of major concern for the conservation of threatened species, and inbreeding avoidance is thought to be a key driver in the evolution of mating systems. However, the estimation of individual inbreeding coefficients in natural populations has been challenging, and, consequently, the full effect of inbreeding on fitness remains unclear. Genomic inbreeding coefficients may resolve the long-standing paucity of data on inbreeding depression in adult traits and total fitness. Here we investigate inbreeding depression in a range of life history traits and fitness in a wild population of red deer (Cervus elaphus) in Scotland using individual inbreeding coefficients derived from dense Single-Nucleotide Polymorphism (SNP) data ([Formula: see text]). We find associations between [Formula: see text] and annual breeding success in both sexes, and between maternal inbreeding coefficient and offspring survival. We also confirm previous findings of inbreeding depression in birth weight and juvenile survival. In contrast, inbreeding coefficients calculated from a deep and comparatively complete pedigree detected inbreeding depression in juvenile survival, but not in any adult fitness component. The total effect of inbreeding on lifetime breeding success (LBS) was substantial in both sexes: for [Formula: see text] [Formula: see text] , a value resulting from a half-sib mating, LBS declined by 72% for females and 95% for males. Our results demonstrate that SNP-based estimates of inbreeding provide a powerful tool for evaluating inbreeding depression in natural populations, and suggest that, to date, the prevalence of inbreeding depression in adult traits may have been underestimated

Circadian-Related Sleep Disorders and Sleep Medication Use in the New Zealand Blind Population: An Observational Prevalence Survey

STUDY OBJECTIVES: To determine the prevalence of self-reported circadian-related sleep disorders, sleep medication and melatonin use in the New Zealand blind population. DESIGN: A telephone survey incorporating 62 questions on sleep habits and medication together with validated questionnaires on sleep quality, chronotype and seasonality. PARTICIPANTS: PARTICIPANTS WERE GROUPED INTO: (i) 157 with reduced conscious perception of light (RLP); (ii) 156 visually impaired with no reduction in light perception (LP) matched for age, sex and socioeconomic status, and (iii) 156 matched fully-sighted controls (FS). SLEEP HABITS AND DISTURBANCES: The incidence of sleep disorders, daytime somnolence, insomnia and sleep timing problems was significantly higher in RLP and LP compared to the FS controls (p<0.001). The RLP group had the highest incidence (55%) of sleep timing problems, and 26% showed drifting sleep patterns (vs. 4% FS). Odds ratios for unconventional sleep timing were 2.41 (RLP) and 1.63 (LP) compared to FS controls. For drifting sleep patterns, they were 7.3 (RLP) and 6.0 (LP). MEDICATION USE: Zopiclone was the most frequently prescribed sleep medication. Melatonin was used by only 4% in the RLP group and 2% in the LP group. CONCLUSIONS: Extrapolations from the current study suggest that 3,000 blind and visually impaired New Zealanders may suffer from circadian-related sleep problems, and that of these, fewer than 15% have been prescribed melatonin. This may represent a therapeutic gap in the treatment of circadian-related sleep disorders in New Zealand, findings that may generalize to other countries

The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis

Background & Aims: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis. Methods: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting–purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis. Results: Our lineage-tracing studies revealed that in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor β was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB–IL34/CCL8 signaling that promotes macrophage chemotaxis. Conclusions: In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC

ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression

Metastatic cancer is extremely difficult to treat, and the presence of metastases greatly reduces a cancer patient’s likelihood of long-term survival. The ZEB1 transcriptional repressor promotes metastasis through downregulation of microRNAs (miRs) that are strong inducers of epithelial differentiation and inhibitors of stem cell factors. Given that each miR can target multiple genes with diverse functions, we posited that the prometastatic network controlled by ZEB1 extends beyond these processes. We tested this hypothesis using a mouse model of human lung adenocarcinoma metastasis driven by ZEB1, human lung carcinoma cells, and human breast carcinoma cells. Transcriptional profiling studies revealed that ZEB1 controls the expression of numerous oncogenic and tumor-suppressive miRs, including miR-34a. Ectopic expression of miR-34a decreased tumor cell invasion and metastasis, inhibited the formation of promigratory cytoskeletal structures, suppressed activation of the RHO GTPase family, and regulated a gene expression signature enriched in cytoskeletal functions and predictive of outcome in human lung adenocarcinomas. We identified several miR-34a target genes, including Arhgap1, which encodes a RHO GTPase activating protein that was required for tumor cell invasion. These findings demonstrate that ZEB1 drives prometastatic actin cytoskeletal remodeling by downregulating miR-34a expression and provide a compelling rationale to develop miR-34a as a therapeutic agent in lung cancer patients.Young-Ho Ahn, Don L. Gibbons, Deepavali Chakravarti, Chad J. Creighton, Zain H. Rizvi, Henry P. Adams, Alexander Pertsemlidis, Philip A. Gregory, Josephine A. Wright, Gregory J. Goodall, Elsa R. Flores and Jonathan M. Kuri

Trends and variation in the management of oesophagogastric cancer patients: a population-based survey

<p>Abstract</p> <p>Background</p> <p>Previous evidence indicates potential variation in the quality of care of cancer patients. We aimed to examine whether recent changes in the treatment of oesophagogastric cancers have been distributed equally among different patient subgroups.</p> <p>Methods</p> <p>We analysed population-based cancer registry data about the treatment patterning of oesophagogastric cancer (other than oesophageal squamous cell carcinoma) during 1995-2006.</p> <p>Results</p> <p>There were 14,077 patients aged ≥40 years (69% men). There was only limited information on stage, and no information on co-morbidity status. During successive triennia, curative surgery use decreased from 28% to 20% (p < 0.001) whilst chemotherapy use increased from 9% to 30% (p < 0.001). Use of palliative surgery and of radiotherapy increased significantly but modestly (7% to 10%, and 9% to 11%, respectively). In multivariable logistic regression adjusting for age group, gender, diagnosis period and tumour type, curative surgery and chemotherapy were used less frequently in more deprived patients [per increasing deprivation group Odds Ratio (OR) = 0.96, 95% Confidence Interval (CI) 0.93-0.99, and OR = 0.90, 95%CI 0.87-0.93, respectively, p < 0.001 for both)]. Chemotherapy was also used less frequently in women (OR = 0.76, p < 0.001).</p> <p>Conclusions</p> <p>During the study period, curative surgery decreased by a third and chemotherapy use increased by more than three-fold, reflecting improvements in the appropriateness and quality of management, but chemotherapy use, in particular, was unequal, both by socioeconomic status and gender.</p

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Globally, functional traits are weak predictors of juvenile tree growth, and we do not know why

1. Plant functional traits, in particular specific leaf area (SLA), wood density and seed mass, are often good predictors of individual tree growth rates within communities. Individuals and species with high SLA, low wood density and small seeds tend to have faster growth rates. 2. If community-level relationships between traits and growth have general predictive value, then similar relationships should also be observed in analyses that integrate across taxa, biogeographic regions and environments. Such global consistency would imply that traits could serve as valuable proxies for the complex suite of factors that determine growth rate, and, therefore, could underpin a new generation of robust dynamic vegetation models. Alternatively, growth rates may depend more strongly on the local environment or growth–trait relationships may vary along environmental gradients. 3. We tested these alternative hypotheses using data on 27 352 juvenile trees, representing 278 species from 27 sites on all forested continents, and extensive functional trait data, 38% of which were obtained at the same sites at which growth was assessed. Data on potential evapotranspiration (PET), which summarizes the joint ecological effects of temperature and precipitation, were obtained from a global data base. 4. We estimated size-standardized relative height growth rates (SGR) for all species, then related them to functional traits and PET using mixed-effect models for the fastest growing species and for all species together. 5. Both the mean and 95th percentile SGR were more strongly associated with functional traits than with PET. PET was unrelated to SGR at the global scale. SGR increased with increasing SLA and decreased with increasing wood density and seed mass, but these traits explained only 3.1% of the variation in SGR. SGR–trait relationships were consistently weak across families and biogeographic zones, and over a range of tree statures. Thus, the most widely studied functional traits in plant ecology were poor predictors of tree growth over large scales. 6. Synthesis. We conclude that these functional traits alone may be unsuitable for predicting growth of trees over broad scales. Determining the functional traits that predict vital rates under specific environmental conditions may generate more insight than a monolithic global relationship can offer

Improved reference genome uncovers novel sex-linked regions in the Guppy (Poecilia reticulata)

This is the author accepted manuscript. The final version is available on open access from Oxford University Press via the DOI in this recordData availability: Population genomics data are available on ENA: Study: PRJEB10680 PCR-free data are available on ENA: Study PRJEB36450 Genome assembly is available on ENA ID: PRJEB36704; ERP119926 All scripts and pipelines are available on github: https://github.com/bfrasercommits/guppy_genomeTheory predicts that the sexes can achieve greater fitness if loci with sexually antagonistic polymorphisms become linked to the sex determining loci, and this can favour the spread of reduced recombination around sex determining regions. Given that sex-linked regions are frequently repetitive and highly heterozygous, few complete Y chromosome assemblies are available to test these ideas. The guppy system (Poecilia reticulata) has long been invoked as an example of sex chromosome formation resulting from sexual conflict. Early genetics studies revealed that male colour patterning genes are mostly but not entirely Y-linked, and that X-linkage may be most common in low predation populations. More recent population genomic studies of guppies have reached varying conclusions about the size and placement of the Y-linked region. However, this previous work used a reference genome assembled from short-read sequences from a female guppy. Here, we present a new guppy reference genome assembly from a male, using long-read PacBio single-molecule real-time sequencing (SMRT) and chromosome contact information. Our new assembly sequences across repeat- and GC-rich regions and thus closes gaps and corrects mis-assemblies found in the short-read female-derived guppy genome. Using this improved reference genome, we then employed broad population sampling to detect sex differences across the genome. We identified two small regions that showed consistent male-specific signals. Moreover, our results help reconcile the contradictory conclusions put forth by past population genomic studies of the guppy sex chromosome. Our results are consistent with a small Y-specific region and rare recombination in male guppies.Max Planck SocietyEuropean Research Council (ERC)Natural Environment Research Council (NERC