Paracrine effects of oocyte secreted factors and stem cell factor on porcine granulosa and theca cells in vitro

Oocyte control of granulosa and theca cell function may be mediated by several growth factors via a local feedback loop(s) between these cell types. This study examined both the role of oocyte-secreted factors on granulosa and thecal cells, cultured independently and in co-culture, and the effect of stem cell factor (SCF); a granulosa cell derived peptide that appears to have multiple roles in follicle development. Granulosa and theca cells were isolated from 2–6 mm healthy follicles of mature porcine ovaries and cultured under serum-free conditions, supplemented with: 100 ng/ml LR3 IGF-1, 10 ng/ml insulin, 100 ng/ml testosterone, 0–10 ng/ml SCF, 1 ng/ml FSH (granulosa), 0.01 ng/ml LH (theca) or 1 ng/ml FSH and 0.01 ng/ml LH (co-culture) and with/without oocyte conditioned medium (OCM) or 5 oocytes. Cells were cultured in 96 well plates for 144 h, after which viable cell numbers were determined. Medium was replaced every 48 h and spent medium analysed for steroids. Oocyte secreted factors were shown to stimulate both granulosa cell proliferation (P < 0.001) and oestradiol production (P < 0.001) by granulosa cells throughout culture. In contrast, oocyte secreted factors suppressed granulosa cell progesterone production after both 48 and 144 hours (P < 0.001). Thecal cell numbers were increased by oocyte secreted factors (P = 0.02), together with a suppression in progesterone and androstenedione synthesis after 48 hours (P < 0.001) and after 144 hours (P = 0.02), respectively. Oocyte secreted factors also increased viable cell numbers (P < 0.001) in co-cultures together with suppression of progesterone (P < 0.001) and oestradiol (P < 0.001). In granulosa cell only cultures, SCF increased progesterone production in a dose dependent manner (P < 0.001), whereas progesterone synthesis by theca cells was reduced in a dose dependent manner (P = 0.002). Co-cultured cells demonstrated an increase in progesterone production with increasing SCF dose (P < 0.001) and an increase in oestradiol synthesis at the highest dose of SCF (100 ng/ml). In summary, these findings demonstrate the presence of a co-ordinated paracrine interaction between somatic cells and germ cells, whereby oocyte derived signals interact locally to mediate granulosa and theca cell function. SCF has a role in modulating this local interaction. In conclusion, the oocyte is an effective modulator of granulosa-theca interactions, one role being the inhibition of luteinization

A major QTL corresponding to the Rk locus for resistance to root-knot nematodes in cowpea (Vigna unguiculata L. Walp.).

Key messageGenome resolution of a major QTL associated with the Rk locus in cowpea for resistance to root-knot nematodes has significance for plant breeding programs and R gene characterization. Cowpea (Vigna unguiculata L. Walp.) is a susceptible host of root-knot nematodes (Meloidogyne spp.) (RKN), major plant-parasitic pests in global agriculture. To date, breeding for host resistance in cowpea has relied on phenotypic selection which requires time-consuming and expensive controlled infection assays. To facilitate marker-based selection, we aimed to identify and map quantitative trait loci (QTL) conferring the resistance trait. One recombinant inbred line (RIL) and two F2:3 populations, each derived from a cross between a susceptible and a resistant parent, were genotyped with genome-wide single nucleotide polymorphism (SNP) markers. The populations were screened in the field for root-galling symptoms and/or under growth-chamber conditions for nematode reproduction levels using M. incognita and M. javanica biotypes. One major QTL was mapped consistently on linkage group VuLG11 of each population. By genotyping additional cowpea lines and near-isogenic lines derived from conventional backcrossing, we confirmed that the detected QTL co-localized with the genome region associated with the Rk locus for RKN resistance that has been used in conventional breeding for many decades. This chromosomal location defined with flanking markers will be a valuable target in marker-assisted breeding and for positional cloning of genes controlling RKN resistance

Occupational asthma: a review.

Occupational asthma is the most common form of occupational lung disease in the developed world at the present time. In this review, the epidemiology, pathogenesis/mechanisms, clinical presentations, management, and prevention of occupational asthma are discussed. The population attributable risk of asthma due to occupational exposures is considerable. Current understanding of the mechanisms by which many agents cause occupational asthma is limited, especially for low-molecular-weight sensitizers and irritants. The diagnosis of occupational asthma is generally established on the basis of a suggestive history of a temporal association between exposure and the onset of symptoms and objective evidence that these symptoms are related to airflow limitation. Early diagnosis, elimination of exposure to the responsible agent, and early use of inhaled steroids may play important roles in the prevention of long-term persistence of asthma. Persistent occupational asthma is often associated with substantial disability and consequent impacts on income and quality of life. Prevention of new cases is the best approach to reducing the burden of asthma attributable to occupational exposures. Future research needs are identified

Network conduciveness with application to the graph-coloring and independent-set optimization transitions

We introduce the notion of a network's conduciveness, a probabilistically interpretable measure of how the network's structure allows it to be conducive to roaming agents, in certain conditions, from one portion of the network to another. We exemplify its use through an application to the two problems in combinatorial optimization that, given an undirected graph, ask that its so-called chromatic and independence numbers be found. Though NP-hard, when solved on sequences of expanding random graphs there appear marked transitions at which optimal solutions can be obtained substantially more easily than right before them. We demonstrate that these phenomena can be understood by resorting to the network that represents the solution space of the problems for each graph and examining its conduciveness between the non-optimal solutions and the optimal ones. At the said transitions, this network becomes strikingly more conducive in the direction of the optimal solutions than it was just before them, while at the same time becoming less conducive in the opposite direction. We believe that, besides becoming useful also in other areas in which network theory has a role to play, network conduciveness may become instrumental in helping clarify further issues related to NP-hardness that remain poorly understood

Safety and Activity of PolyPEPI1018 Combined with Maintenance Therapy in Metastatic Colorectal Cancer: an Open-Label, Multicenter, Phase Ib Study

Purpose: Although chemotherapy is standard of care for met- astatic colorectal cancer (mCRC), immunotherapy has no role in microsatellite stable (MSS) mCRC, a “cold” tumor. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine derived from 7 tumor- associated antigens (TAA) frequently expressed in mCRC. This study assessed PolyPEPI1018 combined with first-line maintenance therapy in patients with MSS mCRC. Patients and Methods: Eleven patients with MSS mCRC received PolyPEPI1018 and Montanide ISA51VG adjuvant subcutaneously, combined with fluoropyrimidine/biologic follow- ing first-line induction with chemotherapy and a biologic (NCT03391232). In Part A of the study, 5 patients received a single dose; in Part B, 6 patients received up to three doses of Poly- PEPI1018 every 12 weeks. The primary objective was safety; sec- ondary objectives were preliminary efficacy, immunogenicity at peripheral and tumor level, and immune correlates. Results: PolyPEPI1018 vaccination was safe and well tolerated. No vaccine-related serious adverse event occurred. Eighty percent of patients had CD8þ T-cell responses against ≥3 TAAs. Increased density of tumor-infiltrating lymphocytes were detected post- treatment for 3 of 4 patients’ liver biopsies, combined with increased expression of immune-related gene signatures. Three patients had objective response according to RECISTv1.1, and 2 patients qual- ified for curative surgery. Longer median progression-free survival for patients receiving multiple doses compared with a single dose (12.5 vs. 4.6 months; P 1⁄4 0.017) suggested a dose–efficacy correlation. The host HLA genotype predicted multi-antigen– specific T-cell responses (P 1⁄4 0.01) indicative of clinical outcome. Conclusions: PolyPEPI1018 added to maintenance chemother- apy for patients with unresectable, MSS mCRC was safe and associated with specific immune responses and antitumor activity warranting further confirmation in a randomized, controlled setting

Readmission and overstay after day case nasal surgery

BACKGROUND: A readmission is classified as a patient necessitating readmission to hospital due to a post-operative complication following discharge. An overstay however, is classified as a patient having to stay longer than the planned duration in hospital (not having been discharged in the interim) due to a post-operative complication. This study aims to investigate patient-related factors that predispose to readmission or overstay and thus make recommendations to decrease the likelihood of readmission or overstay. METHOD: In this retrospective study 312 'day-case nasal procedures', were selected from a total cohort of 4274 ENT patients over a 17-month period. This sub-group was investigated for a range of demographic factors including, age, gender and ethnicity with regards to their relationship to readmission rates and overstay frequency and duration. RESULTS: The rates were 2.88% and 9.62% for readmission and overstay respectively. The total number of days spent in hospital as a result of readmission was 27. Epistaxis was the leading cause for readmission/overstay (28.9%) followed by high levels of post-operative pain preventing them from being discharged (23.7%). All procedures in this study had readmission rates that were below those recommended in the guidelines set by the Royal College of Surgeons of England. Women overstayed significantly longer (t = 1.65, p < 0.05) than men. CONCLUSIONS: Suitable candidates for day-case ENT surgery highlighted by this study include healthy individuals between the ages of 20 and 60. Operating in the morning would increase the immediate post-operative recovery time, which may reduce the numbers of patients who complain of high levels of pain at the time of discharge. Procedures such as septorhinoplasty being performed routinely in the ambulatory setting require additional research into more effective methods of pain control. Standards need to be improved so that the causes of overstay and readmission are clearly identifiable in patient records

A Minimal Threshold of c-di-GMP Is Essential for Fruiting Body Formation and Sporulation in Myxococcus xanthus

Generally, the second messenger bis-(3’-5’)-cyclic dimeric GMP (c-di-GMP) regulates the switch between motile and sessile lifestyles in bacteria. Here, we show that c-di-GMP is an essential regulator of multicellular development in the social bacterium Myxococcus xanthus. In response to starvation, M. xanthus initiates a developmental program that culminates in formation of spore-filled fruiting bodies. We show that c-di-GMP accumulates at elevated levels during development and that this increase is essential for completion of development whereas excess c-di-GMP does not interfere with development. MXAN3735 (renamed DmxB) is identified as a diguanylate cyclase that only functions during development and is responsible for this increased c-di-GMP accumulation. DmxB synthesis is induced in response to starvation, thereby restricting DmxB activity to development. DmxB is essential for development and functions downstream of the Dif chemosensory system to stimulate exopolysaccharide accumulation by inducing transcription of a subset of the genes encoding proteins involved in exopolysaccharide synthesis. The developmental defects in the dmxB mutant are non-cell autonomous and rescued by co-development with a strain proficient in exopolysaccharide synthesis, suggesting reduced exopolysaccharide accumulation as the causative defect in this mutant. The NtrC-like transcriptional regulator EpsI/Nla24, which is required for exopolysaccharide accumulation, is identified as a c-diGMP receptor, and thus a putative target for DmxB generated c-di-GMP. Because DmxB can be—at least partially—functionally replaced by a heterologous diguanylate cyclase, these results altogether suggest a model in which a minimum threshold level of c-di-GMP is essential for the successful completion of multicellular development in M. xanthus

Extragalactic Radio Continuum Surveys and the Transformation of Radio Astronomy

Next-generation radio surveys are about to transform radio astronomy by discovering and studying tens of millions of previously unknown radio sources. These surveys will provide new insights to understand the evolution of galaxies, measuring the evolution of the cosmic star formation rate, and rivalling traditional techniques in the measurement of fundamental cosmological parameters. By observing a new volume of observational parameter space, they are also likely to discover unexpected new phenomena. This review traces the evolution of extragalactic radio continuum surveys from the earliest days of radio astronomy to the present, and identifies the challenges that must be overcome to achieve this transformational change.Comment: To be published in Nature Astronomy 18 Sept 201

Reliability and Validity of the Ethiopian Version of the Hospital Anxiety and Depression Scale (HADS) in HIV Infected Patients

The hospital anxiety and depression scale (HADS) is a widely used instrument for evaluating psychological distress from anxiety and depression. HADS has not yet been validated in Ethiopia. The aim of this study was to evaluate the reliability and validity of the Amharic (Ethiopian language) version of HADs among HIV infected patients.The translated scale was administered to 302 HIV/AIDS patients on follow up for and taking anti-retroviral treatment. Consistency assessment was conducted using Cronbach's alpha, test-retest reliability using intra-class correlation coefficients (ICC). Construct validity was examined using principal components analysis (PCA). Parallel analysis, Kaiser's criterion and the scree test were used for factor extraction.The internal consistency was 0.78 for the anxiety, 0.76 for depression subscales and 0.87 for the full scale of HADS. The intra-class correlation coefficient (ICC) was 80%, 86%, and 84% for the anxiety and depression subscales, and total score respectively. PCA revealed a one dimensional scale.This preliminary validation study of the Ethiopian version of the HADs indicates that it has promising acceptability, reliability and validity. The adopted scale has a single underlying dimension as indicated by Razavi's model. The HADS can be used to examine psychological distress in HIV infected patients. Findings are discussed and recommendations made