Regulatory complexity revealed by integrated cytological and RNA-seq analyses of meiotic substages in mouse spermatocytes

BACKGROUND: The continuous and non-synchronous nature of postnatal male germ-cell development has impeded stage-specific resolution of molecular events of mammalian meiotic prophase in the testis. Here the juvenile onset of spermatogenesis in mice is analyzed by combining cytological and transcriptomic data in a novel computational analysis that allows decomposition of the transcriptional programs of spermatogonia and meiotic prophase substages. RESULTS: Germ cells from testes of individual mice were obtained at two-day intervals from 8 to 18 days post-partum (dpp), prepared as surface-spread chromatin and immunolabeled for meiotic stage-specific protein markers (STRA8, SYCP3, phosphorylated H2AFX, and HISTH1T). Eight stages were discriminated cytologically by combinatorial antibody labeling, and RNA-seq was performed on the same samples. Independent principal component analyses of cytological and transcriptomic data yielded similar patterns for both data types, providing strong evidence for substage-specific gene expression signatures. A novel permutation-based maximum covariance analysis (PMCA) was developed to map co-expressed transcripts to one or more of the eight meiotic prophase substages, thereby linking distinct molecular programs to cytologically defined cell states. Expression of meiosis-specific genes is not substage-limited, suggesting regulation of substage transitions at other levels. CONCLUSIONS: This integrated analysis provides a general method for resolving complex cell populations. Here it revealed not only features of meiotic substage-specific gene expression, but also a network of substage-specific transcription factors and relationships to potential target genes. BMC Genomics 2016 Aug 12; 17(1):628

Erythropoeitin dose variation in different facilities in different countries and its relationship to drug resistance Management of comorbidities in kidney disease in the 21st century: Anemia and bone disease

Erythropoeitin dose variation in different facilities in different countries and its relationship to drug resistance.BackgroundThe correction of anemia using erythropoeitin (EPO) is accorded high priority in the management of patients undergoing hemodialysis (HD). Target hemoglobin (Hb) levels have been established in many countries. Following an observation that the mean facility EPO dose in a chain of facilities in the United States varied by more than two-fold, an examination of the practice of anemia correction in other settings was carried out.MethodsWe reviewed demographic and laboratory parameters in prevalent HD patients in 50 United States facilities and in a single HD facility in Vicenza, Italy. The mean EPO dose profile of the United States facilities was compared with the profiles in 10 facilities in the eastern United Kingdom (UKER) and in 20 facilities reporting to the United Kingdom Renal Registry (UKRR). Analysis of the factors that correlate with EPO resistance was carried out using the United States and Italian data.ResultsThe average EPO doses, by facility, in the 51 United States, the 10 UKER, and the 19 UKRR facilities were 19,569, 8,416, and 7,992 international units per week (IU/wk), respectively. While examination of the UKRR revealed a similar degree of inter-facility variation (2.6-fold), much larger doses of EPO were being administered in the United States patients, particularly in the low Hb group. Multivariate analysis of the United States data suggested that factors related to inflammation, including low albumin, the use of tunneled catheters for vascular access, and low protein catabolic rate (enPCR) correlated with low Hb and relative EPO resistance.ConclusionDespite similar guidelines for anemia management, significant differences in practice are observed. While there seems to be a reluctance to administer large EPO doses to individual patients in Europe, this does not seem to apply in the United States, where more EPO is given. EPO resistance seems relative rather than absolute in many patients, allowing some to respond to the higher doses

Stresses and strains on the human fetal skeleton during development

Mechanical forces generated by fetal kicks and movements result in stimulation of the fetal skeleton in the form of stress and strain. This stimulation is known to be critical for prenatal musculoskeletal development; indeed, abnormal or absent movements have been implicated in multiple congenital disorders. However, the mechanical stress and strain experienced by the developing human skeleton in utero have never before been characterized. Here, we quantify the biomechanics of fetal movements during the second half of gestation by modelling fetal movements captured using novel cine-magnetic resonance imaging technology. By tracking these movements, quantifying fetal kick and muscle forces, and applying them to three-dimensional geometries of the fetal skeleton, we test the hypothesis that stress and strain change over ontogeny. We find that fetal kick force increases significantly from 20 to 30 weeks' gestation, before decreasing towards term. However, stress and strain in the fetal skeleton rises significantly over the latter half of gestation. This increasing trend with gestational age is important because changes in fetal movement patterns in late pregnancy have been linked to poor fetal outcomes and musculoskeletal malformations. This research represents the first quantification of kick force and mechanical stress and strain due to fetal movements in the human skeleton in utero, thus advancing our understanding of the biomechanical environment of the uterus. Further, by revealing a potential link between fetal biomechanics and skeletal malformations, our work will stimulate future research in tissue engineering and mechanobiology

A guide to the South Plains of Texas

A compilation of essays and articles covering history, agriculture, educational institutions, and legends of the historic South Plains of Texas.[139] leaves ; 152 pdf pages.November 1935.Pictorial illustrations by Bess Hubbard.Mimeographed copy reproduced by the students of Lubbock High School with permission and assistance of the Texas Highway Dept.Plains of Texas / A.W. Evans -- The rock house on Blanco Canyon / R.B. Smith -- The story of the famous Old Yellow House Ranch / Lamb county news -- The T-Bar Ranch / R.B. Smith -- U-Lazy-S Ranch / E. Taylor -- The old Mackenzie Trail / W.L Chittenden -- Mackenzie's Indian campaigns on the Staked Plains / M.L. Cox -- Horse bones / R.G. Carter -- Old Man Singer's store / W.C. Holden -- Letter of long ago describes living conditions in days of first settles / M. Witt -- Shanties and dugouts / The Cattleman -- The legend of the sand hills / J. Mitchell -- Three notable landmarks in Lynn County / F.P. Hill -- Descriptions of South Plains cities and towns / V. Upton -- Elevation, population, and highway mileage maps / M.W. Hobbs -- Roadside divertissement / V. Upton

Male gays in the female gaze: women who watch m/m pornography

This paper draws on a piece of wide-scale mixed-methods research that examines the motivations behind women who watch gay male pornography. To date there has been very little interdisciplinary research investigating this phenomenon, despite a recent survey by PornHub (one of the largest online porn sites in the world) showing that gay male porn is the second most popular choice for women porn users out of 25+ possible genre choices. While both academic literature and popular culture have looked at the interest that (heterosexual) men have in lesbian pornography, considerably less attention has been paid to the consumption of gay male pornography by women. Research looking at women's consumption of pornography from within the Social Sciences is very focused around heterosexual (and, to a lesser extent, lesbian) pornography. Research looking more generally at gay pornography/erotica (and the subversion of the ‘male gaze’/concept of ‘male as erotic object’) often makes mention of female interest in this area, but only briefly, and often relies on anecdotal or observational evidence. Research looking at women's involvement in slashfic (primarily from within media studies), while very thorough and rich, tends to view slash writing as a somewhat isolated phenomenon (indeed, in her influential article on women's involvement in slash, Bacon-Smith talks about how ‘only a small number’ of female slash writers and readers have any interest in gay literature or pornography more generally, and this phenomenon is not often discussed in more recent analyses of slash); so while there has been a great deal of very interesting research done in this field, little attempt has been made to couch it more generally within women's consumption and use of pornography and erotica or to explore what women enjoy about watching gay male pornography. Through a series of focus groups, interviews, and an online questionnaire (n = 275), this exploratory piece of work looks at what women enjoy about gay male pornography, and how it sits within their consumption of erotica/pornography more generally. The article investigates what this has to say about the existence and nature of a ‘female gaze’

A Randomized Controlled Trial of Folate Supplementation When Treating Malaria in Pregnancy with Sulfadoxine-Pyrimethamine

OBJECTIVES: Sulfadoxine-pyrimethamine (SP) is an antimalarial drug that acts on the folate metabolism of the malaria parasite. We investigated whether folate (FA) supplementation in a high or a low dose affects the efficacy of SP for the treatment of uncomplicated malaria in pregnant women. DESIGN: This was a randomized, placebo-controlled, double-blind trial. SETTING: The trial was carried out at three hospitals in western Kenya. PARTICIPANTS: The participants were 488 pregnant women presenting at their first antenatal visit with uncomplicated malaria parasitaemia (density of ≥ 500 parasites/μl), a haemoglobin level higher than 7 g/dl, a gestational age between 17 and 34 weeks, and no history of antimalarial or FA use, or sulfa allergy. A total of 415 women completed the study. INTERVENTIONS: All participants received SP and iron supplementation. They were randomized to the following arms: FA 5 mg, FA 0.4 mg, or FA placebo. After 14 days, all participants continued with FA 5 mg daily as per national guidelines. Participants were followed at days 2, 3, 7, 14, 21, and 28 or until treatment failure. OUTCOME MEASURES: The outcomes were SP failure rate and change in haemoglobin at day 14. RESULTS: The proportion of treatment failure at day 14 was 13.9% (19/137) in the placebo group, 14.5% (20/138) in the FA 0.4 mg arm (adjusted hazard ratio [AHR], 1.07; 98.7% confidence interval [CI], 0.48 to 2.37; p = 0.8), and 27.1% (38/140) in the FA 5 mg arm (AHR, 2.19; 98.7% CI, 1.09 to 4.40; p = 0.005). The haemoglobin levels at day 14 were not different relative to placebo (mean difference for FA 5 mg, 0.17 g/dl; 98.7% CI, −0.19 to 0.52; and for FA 0.4 mg, 0.14 g/dl; 98.7% CI, −0.21 to 0.49). CONCLUSIONS: Concomitant use of 5 mg FA supplementation compromises the efficacy of SP for the treatment of uncomplicated malaria in pregnant women. Countries that use SP for treatment or prevention of malaria in pregnancy need to evaluate their antenatal policy on timing or dose of FA supplementation

Pennsylvania Folklife Vol. 18, No. 1

• Tanning in Chester County, Pennsylvania, 1711-1850 • Chester County Widow Wills (1714-1800), A Folklife Source • Folk Elements in Scotch-Irish Presbyterian Communities • The Thomas Massey House • Passengers on the Ketch Endeavour • The Medical Plants of Berks County, Pennsylvania • Notes and Documents: A Dunkard Love Feast ; Jacob Graeff\u27s Reminiscences of Reading • Symposium on the Pennsylvania Dutch Dialect • Farm Dress: Folk-Cultural Questionnaire No. 9https://digitalcommons.ursinus.edu/pafolklifemag/1033/thumbnail.jp

Multi-modality machine learning predicting Parkinson's disease

Personalized medicine promises individualized disease prediction and treatment. The convergence of machine learning (ML) and available multimodal data is key moving forward. We build upon previous work to deliver multimodal predictions of Parkinson's disease (PD) risk and systematically develop a model using GenoML, an automated ML package, to make improved multi-omic predictions of PD, validated in an external cohort. We investigated top features, constructed hypothesis-free disease-relevant networks, and investigated drug-gene interactions. We performed automated ML on multimodal data from the Parkinson's progression marker initiative (PPMI). After selecting the best performing algorithm, all PPMI data was used to tune the selected model. The model was validated in the Parkinson's Disease Biomarker Program (PDBP) dataset. Our initial model showed an area under the curve (AUC) of 89.72% for the diagnosis of PD. The tuned model was then tested for validation on external data (PDBP, AUC 85.03%). Optimizing thresholds for classification increased the diagnosis prediction accuracy and other metrics. Finally, networks were built to identify gene communities specific to PD. Combining data modalities outperforms the single biomarker paradigm. UPSIT and PRS contributed most to the predictive power of the model, but the accuracy of these are supplemented by many smaller effect transcripts and risk SNPs. Our model is best suited to identifying large groups of individuals to monitor within a health registry or biobank to prioritize for further testing. This approach allows complex predictive models to be reproducible and accessible to the community, with the package, code, and results publicly available

Pennsylvania Folklife Vol. 18, No. 1

• Tanning in Chester County, Pennsylvania, 1711-1850 • Chester County Widow Wills (1714-1800), A Folklife Source • Folk Elements in Scotch-Irish Presbyterian Communities • The Thomas Massey House • Passengers on the Ketch Endeavour • The Medical Plants of Berks County, Pennsylvania • Notes and Documents: A Dunkard Love Feast ; Jacob Graeff\u27s Reminiscences of Reading • Symposium on the Pennsylvania Dutch Dialect • Farm Dress: Folk-Cultural Questionnaire No. 9https://digitalcommons.ursinus.edu/pafolklifemag/1033/thumbnail.jp