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Perkins reviews The Book of Abish by Mette Harrison.

Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities. Metabolic profiling was performed on diet-induced obese (DIO) mice, lean mice, and DIO mice that underwent sleeve gastrectomies (SGx). In addition, mice were subjected to intraperitoneal (i.p.) injections with taurodeoxycholic acid (TDCA) and valine. Indirect calorimetry was performed to assess food intake and energy expenditure. Expression of appetite-regulating hormones was assessed through quantification of isolated RNA from dissected hypothalamus tissue. Subsequently, i.p. injections with a melanin-concentrating hormone (MCH) antagonist and intrathecal administration of MCH were performed and weight loss was monitored. Mass spectrometric metabolomic profiling revealed significantly reduced systemic levels of TDCA and L-valine in DIO mice. TDCA and L-valine levels were restored after SGx in both human and mice to levels comparable with lean controls. Systemic treatment with TDCA and valine induced a profound weight loss analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the MCH. In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders. This work has been supported in part by a grant from NIH (UO-1 A1 132898 to S.G.T., DP and MA). M.Q. was supported by the IFB Integrated Research and Treatment Centre Adiposity Diseases (Leipzig, Germany) and the German Research Foundation (QU 420/1-1). J.I. was supported by the Biomedical Education Program (BMEP) of the German Academic Exchange Service (DAAD). T.H. (HE 7457/1-1) and F.K. (KR 4362/1-1) were supported by the German Research Foundation (DFG). H.R.C.B. was supported the Swiss Society of Cardiac Surgery. Y.N. was supported by the Chinese Scholarship Council (201606370196) and Central South University. H.U., T.M. and R.M. were supported by the Osaka Medical Foundation. C.S.F. was supported by the German Research Foundation (DFG, SFB738, B3).

Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias and lymphomas (T-ALL), making this receptor a promising target for drugs such as γ-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates the expression of PTEN (encoding phosphatase and tensin homolog) and the activity of the phosphoinositol-3 kinase (PI3K)-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila melanogaster model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with human T-ALL resistance to pharmacological inhibition of NOTCH1. Overall, these findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.

[...]we hypothesized that alterations in microbiota may also impact lung transplant outcomes, particularly chronic lung allograft rejection, which is characterized by airway remodeling and fibrosis. In the context of skin grafts, we previously showed that pretreatment of both donor and recipient mice with antibiotics prolonged graft survival, but pretreatment of only the donor or only the recipient did not alter graft outcomes (5). [...]continuing antibiotics after transplantation did not further prolong skin graft survival (M.-L.A., unpublished results). [...]we further analyzed T-cell subsets and IL-17 expression to determine whether the protection in lung allograft rejection associated with antibiotic pretreatment was due to a reduction in the IL-17 response. [...]we demonstrate that alterations in microbial diversity are associated with decreased signs of lung allograft rejection, but future studies are needed to determine whether they are sufficient to mediate this effect. ?

Background: Aerosolization of exogenous surfactant remains a challenge. This study is aimed to evaluate the efficacy of atomized poractant alfa (Curosurf) administered with a novel atomizer in preterm lambs with respiratory distress syndrome. Methods: Twenty anaesthetized lambs, 127 ± 1 d gestational age, (mean ± SD) were instrumented before birth and randomized to receive either (i) positive pressure ventilation without surfactant (Control group), (ii) 200 mg/kg of bolus instilled surfactant (Bolus group) at 10 min of life or (iii) 200 mg/kg of atomized surfactant (Atomizer group) over 60 min from 10 min of life. All lambs were ventilated for 180 min with a standardized protocol. Lung mechanics, regional lung compliance (electrical impedance tomography), and carotid blood flow (CBF) were measured with arterial blood gas analysis. Results: Dynamic compliance and oxygenation responses were similar in the Bolus and Atomizer groups, and both better than Control by 180 min (all P < 0.05; two-way ANOVA). Both surfactant groups demonstrated more homogeneous regional lung compliance throughout the study period. There were no differences in CBF Conclusion: In a preterm lamb model, atomized surfactant resulted in similar gas exchange and mechanics as bolus administration. This study suggests evaluation of supraglottic atomization with this system when noninvasive support is warranted.

Placental site trophoblastic tumor (PSTT) is a neoplastic proliferation of intermediate trophoblasts that invades the myometrium at the placental site after a pregnancy. Less than 100 cases have been reported. Information of the sex assignment of the antecedent gestation is available in 21 cases: 18 of these were female. To explore this interesting phenomenon, we have determined the sex chromosome composition of the tumor tissue preserved in paraffin blocks for five new cases of this condition. The last documented gestational event included a normal vaginal delivery of female infants in three cases, normal vaginal delivery of an infant of unknown sex in one case and a molar gestation in one case. Using the X-linked human androgen receptor (AR) gene as a polymorphic marker, we showed that in all five cases the tumor had a likely XX chromosomal composition; and in four cases it was possible to determine that one of the X chromosomes was of paternal origin. In one case, the paternal X chromosome showed no polymorphism to either maternal X chromosomes. In addition, sensitive semi-nested PCR failed to show a human Y chromosome element in any of the five cases of PSTT. Overall, of 21 cases from the literature and 5 cases of ours, 89% (23 of 26) showed an XX genomic composition in PSTT, either by history or genetic analysis. These results suggest that most PSTT were derived from the antecedent female conceptus and were likely to have possessed a functional paternal X chromosome. Methylation status analysis at the AR locus was performed in the three PSTT in which the paternal X chromosome was identifiable. In two cases, the paternal AR locus was hypomethylated while the corresponding maternal locus was hypermethylated. The methylation status of other loci was not investigated. Collectively, sex chromosome analysis of five cases of PSTT with literature support suggests a unique genetic basis for the development of PSTT that involves the paternal X chromosome. Although largely speculative, an active paternal X chromosome may be of importance in the pathogenesis of PSTT.

Background. Population health within and between nations is heavily influenced by political determinants, yet these determinants have received significantly less attention than socioeconomic factors in public health. It has been hypothesized that the welfare state, as a political variable, may play a particularly prominent role in affecting both health indicators and health disparities in developed countries. The research, however, provides conflicting evidence regarding the health impact of particular regimes over others and the mechanisms through which the welfare state can most significantly affect health. Objective. To perform a systematic review of the literature as a means of exploring what the current research indicates regarding the benefits or detriments of particular regimes styles and the pathways through which the welfare state can impact heath indicators and health disparities within developed countries. Methods. A thorough search of the EBSCO, Pubmed, Medline, Web of Science, and Scopus electronic databases was conducted and resulted in the identification of 15 studies that evaluated the association between welfare state regime and population health outcomes, and/or pathways through with the welfare state influences health. Results. Social democratic countries tended to perform best when infant mortality rate (IMR) was the primary outcome of interest, whereas liberal countries performed strongly in relation to self perceived health. The results were mixed regarding welfare state effectiveness in mitigating health inequities, with Christian democratic countries performing as well as social democratic countries. In relation to welfare state pathways, public health spending and medical coverage were associated with positive health indicators. Redistributive impact of the welfare state was also consistently associated with better health outcomes while social security expenditures were not. Discussion/Conclusions. Studies consistently discovered a significant relationship between the welfare state and population health and/or health disparities, lending support to the hypothesis that the welfare state is, indeed, an important non-medical determinant of health. However, it is still fairly unclear which welfare state regime may be most protective for health, as results varied according to the measured health indicator. The research regarding welfare state pathways is particularly undeveloped, and does not provide much insight into the importance of in-kind service provision or cash transfers, or targeted or universal approaches to the welfare state. Suggestions to direct future research are provided.