Moving from immune phenotyping of colorectal cancer to mechanistic insights on aspirin use

Colorectal cancer is the third most common cancer in men and women in the US, with over 95,000 new cases expected in 2016. Many preclinical, epidemiological, and clinical studies have shown that regular aspirin (acetylsalicylic acid) use, even in low-doses, prevents the development of colorectal neoplasia. In 2015, the US Preventative Services Task Force acknowledged the value of low-dose aspirin in primary prevention of colorectal cancer in adults aged 50–59 years. Despite this wealth of evidence, how aspirin reduces colorectal cancer risk is not fully understood. Many mechanisms have been proposed, but the most commonly cited is aspirin’s inhibition of PTGS2 (COX-2), a known mediator of inflammation and immunosuppression that is overexpressed in many colorectal neoplasms

Involvement of angiotensin II in the remodeling induced by a chronic decrease in blood flow in rat mesenteric resistance arteries

Blood flow reduction induces inward remodeling of resistance arteries (RAs). This remodeling occurs in ischemic diseases, diabetes and hypertension. Nonetheless, the effect of flow reduction per se, independent of the effect of pressure or metabolic influences, is not well understood in RA. As angiotensin II is involved in the response to flow in RA, we hypothesized that angiotensin II may also be involved in the remodeling induced by a chronic flow reduction. We analyzed the effect of angiotensin I-converting enzyme inhibition (perindopril) and angiotensin II type 1 receptor blockade (candesartan) on inward remodeling induced by blood flow reduction in vivo in rat mesenteric RAs (low flow (LF) arteries). After 1 week, diameter reduction in LF arteries was associated with reduced endothelium-dependent relaxation and lower levels of eNOS expression. Superoxide production and extracellular signal-regulated kinases 1/2 (ERK1/2 phosphorylation were higher in LF than in normal flow arteries. Nevertheless, the absence of eNOS or superoxide level reduction (tempol or apocynin) did not prevent LF remodeling. Perindopril and candesartan prevented inward remodeling in LF arteries. Contractility to angiotensin II was reduced in LF vessels by perindopril, candesartan and the ERK1/2 blocker PD98059. ERK1/2 activation (ratio phospho-ERK/ERK) was higher in LF arteries, and this activation was prevented by perindopril and candesartan. ERK1/2 inhibition in vivo (U0126) prevented LF-induced diameter reduction. Thus, inward remodeling because of blood flow reduction in mesenteric RA depends on unopposed angiotensin II-induced contraction and ERK1/2 activation, independent of superoxide production. These findings might be of importance in the treatment of vascular disorders

Sex and age differences in "theory of mind" across 57 countries using the English version of the "Reading the Mind in the Eyes" Test.

The "Reading the Mind in the Eyes" Test (Eyes Test) is a widely used assessment of "theory of mind." The NIMH Research Domain Criteria recommends it as one of two tests for "understanding mental states." Previous studies have demonstrated an on-average female advantage on the Eyes Test. However, it is unknown whether this female advantage exists across the lifespan and across a large number of countries. Thus, we tested sex and age differences using the English version of the Eyes Test in adolescents and adults across 57 countries. We also tested for associations with sociodemographic and cognitive/personality factors. We leveraged one discovery dataset (N = 305,726) and three validation datasets (Ns = 642; 5,284; and 1,087). The results show that: i) there is a replicable on-average female advantage in performance on the Eyes Test; ii) performance increases through adolescence and shallowly declines across adulthood; iii) the on-average female advantage is evident across the lifespan; iv) there is a significant on-average female advantage in 36 out of 57 countries; v) there is a significant on-average female advantage on translated (non-English) versions of the Eyes Test in 12 out of 16 countries, as confirmed by a systematic review; vi) D-scores, or empathizing-systemizing, predict Eyes Test performance above and beyond sex differences; and vii) the female advantage is negatively linked to "prosperity" and "autonomy," and positively linked to "collectivism," as confirmed by exploratory country-level analyses. We conclude that the on-average female advantage on the Eyes Test is observed across ages and most countries

ClbP is a prototype of a peptidase subgroup involved in biosynthesis of nonribosomal peptides

The pks genomic island of Escherichia coli encodes polyketide (PK) and nonribosomal peptide (NRP) synthases that allow assembly of a putative hybrid PK-NRP compound named colibactin that induces DNA double-strand breaks in eukaryotic cells. The pks-encoded machinery harbors an atypical essential protein, ClbP. ClbP crystal structure and mutagenesis experiments revealed a serine-active site and original structural features compatible with peptidase activity, which was detected by biochemical assays. Ten ClbP homologs were identified in silico in NRP genomic islands of closely and distantly related bacterial species. All tested ClbP homologs were able to complement a clbP-deficient E. coli mutant. ClbP is therefore a prototype of a new subfamily of extracytoplasmic peptidases probably involved in the maturation of NRP compounds. Such peptidases will be powerful tools for the manipulation of NRP biosynthetic pathways

Construction of a doxycycline inducible adipogenic lentiviral expression system

To provide a tool for research on regulating adipocyte differentiation, tetracycline inducible (Tet on) lentiviral expression vectors under the control of an adipose-specific promoter were constructed. The lowest basal expression in the absence of doxycycline and most efficient dose-dependent, doxycycline-induced transient overexpression was observed using vectors constructed with a combination of Tetracycline Responsive Element (TRE) and reverse tetracycline-controlled TransActivator advanced (rtTAadv), transfected in white (3T3-L1) and brown (HIB-1B) preadipocytes cell lines. The results demonstrate that doxycycline adipogenic inducible expression can be achieved using a pLenti TRE / rtTA adv under the control of the truncated aP2 promoter in HIB-1B preadipocytes

Efficacy and safety of ITCA 650, a novel drug-Device GLP-1 receptor agonist, in type 2 diabetes uncontrolled with oral antidiabetes drugs: The FREEDOM-1 trial

OBJECTIVE ITCA 650 (exenatide in osmotic mini-pump) continuously delivers exenatide subcutaneously for 3–6 months. Two doses of ITCA 650 were compared with placebo in patients with uncontrolled type 2 diabetes. RESEARCH DESIGN AND METHODS This 39-week, phase 3, double-blind, placebo-controlled trial randomized 460 patients aged 18–80 years with glycated hemoglobin (HbA1c) 7.5–10% [58–86 mmol/mol] 1:1:1 to placebo, ITCA 650 40 mg/day, or ITCA 650 60 mg/day. Primary end point was change in HbA1c at 39 weeks. RESULTS Least squares (LS) mean change from baseline HbA1c was 21.1% [212.2 mmol/mol] and 21.2% [213.2 mmol/mol] for ITCA 650 40 and 60 mg/day, respectively (P < 0.001 vs. placebo 20.1% [21.3 mmol/mol]). In a prespecified analysis, greater HbA1c reductions occurred in patients not receiving sulfonylureas (SUs) versus those receiving SUs (21.7% vs. 21.2% [218.6 and 213.1 mmol/mol]). At week 39, HbA1c <7% [53 mmol/mol] was attained in 37%, 44%, and 9% of ITCA 650 40 mg/day, ITCA 650 60 mg/day, and placebo groups, respectively (P < 0.001 each dose vs. placebo). LS mean change from baseline body weight was 22.3 kg and 23.0 kg for ITCA 650 40 and 60 mg/day, respectively (P £ 0.015 vs. placebo 21.0 kg). Nausea was the most common adverse event (AE) and subsided over time. Discontinuation for gastrointestinal AEs occurred in 7.2% with ITCA and 1.3% with placebo. Most AEs associated with procedures to place and remove ITCA 650 were mild and transient. CONCLUSIONS ITCA 650 significantly reduced HbA1c and weight compared with placebo and was well tolerated in patients with uncontrolled type 2 diabetes on oral antidiabetes medications

Donor states in modulation-doped Si/SiGe heterostructures

We present a unified approach for calculating the properties of shallow donors inside or outside heterostructure quantum wells. The method allows us to obtain not only the binding energies of all localized states of any symmetry, but also the energy width of the resonant states which may appear when a localized state becomes degenerate with the continuous quantum well subbands. The approach is non-variational, and we are therefore also able to evaluate the wave functions. This is used to calculate the optical absorption spectrum, which is strongly non-isotropic due to the selection rules. The results obtained from calculations for Si/Si$_{1-x}$Ge$_x$ quantum wells allow us to present the general behavior of the impurity states, as the donor position is varied from the center of the well to deep inside the barrier. The influence on the donor ground state from both the central-cell effect and the strain arising from the lattice mismatch is carefully considered.Comment: 17 pages, 10 figure

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Observing the First Stars and Black Holes

The high sensitivity of JWST will open a new window on the end of the cosmological dark ages. Small stellar clusters, with a stellar mass of several 10^6 M_sun, and low-mass black holes (BHs), with a mass of several 10^5 M_sun should be directly detectable out to redshift z=10, and individual supernovae (SNe) and gamma ray burst (GRB) afterglows are bright enough to be visible beyond this redshift. Dense primordial gas, in the process of collapsing from large scales to form protogalaxies, may also be possible to image through diffuse recombination line emission, possibly even before stars or BHs are formed. In this article, I discuss the key physical processes that are expected to have determined the sizes of the first star-clusters and black holes, and the prospect of studying these objects by direct detections with JWST and with other instruments. The direct light emitted by the very first stellar clusters and intermediate-mass black holes at z>10 will likely fall below JWST's detection threshold. However, JWST could reveal a decline at the faint-end of the high-redshift luminosity function, and thereby shed light on radiative and other feedback effects that operate at these early epochs. JWST will also have the sensitivity to detect individual SNe from beyond z=10. In a dedicated survey lasting for several weeks, thousands of SNe could be detected at z>6, with a redshift distribution extending to the formation of the very first stars at z>15. Using these SNe as tracers may be the only method to map out the earliest stages of the cosmic star-formation history. Finally, we point out that studying the earliest objects at high redshift will also offer a new window on the primordial power spectrum, on 100 times smaller scales than probed by current large-scale structure data.Comment: Invited contribution to "Astrophysics in the Next Decade: JWST and Concurrent Facilities", Astrophysics & Space Science Library, Eds. H. Thronson, A. Tielens, M. Stiavelli, Springer: Dordrecht (2008

Paternal Age Alters Social Development in Offspring

Objective Advanced paternal age (APA) at conception has been linked with autism and schizophrenia in offspring, neurodevelopmental disorders that affect social functioning. The current study explored the effects of paternal age on social development in the general population. Method We used multilevel growth modeling to investigate APA effects on socioemotional development from early childhood until adolescence, as measured by the Strengths and Difficulties Questionnaire (SDQ) in the Twins Early Development Study (TEDS) sample. We also investigated genetic and environmental underpinnings of the paternal age effects on development, using the Additive genetics, Common environment, unique Environment (ACE) and gene–environment (GxE) models. Results In the general population, both very young and advanced paternal ages were associated with altered trajectory of social development (intercept: p = .01; slope: p = .03). No other behavioral domain was affected by either young or advanced age at fatherhood, suggesting specificity of paternal age effects. Increased importance of genetic factors in social development was recorded in the offspring of older but not very young fathers, suggesting distinct underpinnings of the paternal age effects at these two extremes. Conclusion Our findings highlight that the APA-related deficits that lead to autism and schizophrenia are likely continuously distributed in the population