Embryological stages in the establishing of myeloschisis with spina bifida

No Abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49611/1/1000930304_ftp.pd

Self-Pity: Exploring the Links to Personality, Control Beliefs, and Anger

Self-pity is a frequent response to stressful events. So far, however, empirical research has paid only scant attention to this subject. The present article aims at exploring personality characteristics associated with individual differences in feeling sorry for oneself. Two studies with N = 141 and N = 161 university students were conducted, employing multidimensional measures of personality, control beliefs, anger, loneliness, and adult attachment. With respect to personality, results showed strong associations of self-pity with neuroticism, particularly with the depression facet. With respect to control beliefs, individuals high in self-pity showed generalized externality beliefs, seeing themselves as controlled by both chance and powerful others. With respect to anger expression, self-pity was primarily related to anger-in. Strong connections with anger rumination were also found. Furthermore, individuals high in self-pity reported emotional loneliness and ambivalent-worrisome attachments. Finally, in both studies, a strong correlation with gender was found, with women reporting more self-pity reactions to stress than men. Findings are discussed with respect to how they support, extend, and qualify the previous literature on self-pity, and directions for future empirical research are pointed out

Moral perfectionism and moral values, virtues, and judgments: A preliminary investigation

Moral perfectionism has a long tradition in philosophical inquiry, but so far has been ignored in psychological research. This article presents a first psychological investigation of moral perfectionism exploring its relationships with moral values, virtues, and judgments. In three studies, 539 university students responded to items of the Frost Multidimensional Perfectionism Scale (Frost, Marten, Lahart, & Rosenblate, 1990) adapted to measure personal moral standards (PMS) and concern over moral mistakes (CMM) and completed measures of moral values, virtues, and forgiveness, gratitude, and wrong behavior judgments. When partial correlations were computed controlling for the overlap between PMS and CMM, PMS showed positive correlations with moral values, virtues, reciprocal helping, forgiveness, and condemnation of wrong behaviors. In contrast, CMM showed a positive correlation only with indebtedness and a negative correlation with self-reliance. The present findings, while preliminary, suggest that moral perfectionism is a personality characteristic that may help explain individual differences in moral values, virtues, and judgments

Testing of the Lunar Reconnaissance Orbiter Attitude Control System Re-Design Without a Gyro

The Lunar Reconnaissance Orbiter (LRO) was launched in 2009 and, with itsseven science instruments, has made numerous contributions to our understandingof the moon. LRO is in an elliptical, polar lunar orbit and nominally maintainsa nadir orientation. There are frequent slews off nadir to observe various sciencetargets. LRO attitude control system (ACS) has two star trackers and a gyro forattitude estimation in an extended Kalman filter (EKF) and four reaction wheelsused in a proportional-integral-derivative (PID) controller. LRO is equipped withthrusters for orbit adjustments and momentum management. In early 2018, thegyro was powered off following a fairly rapid decline in the laser intensity on theX axis. Without the gyro, the EKF has been disabled. Attitude is provided by asingle star tracker and a coarse rate estimate is computed by a back differencingof the star tracker quaternions. Slews have also been disabled. A new rate estimationapproach makes use of a complementary filter, combining the quaterniondifferentiated rates and the integrated PID limited control torque (with reactionwheel drag and feedforward torque removed). The filtered rate estimate replacesthe MIMU rate in the EKF, resulting in minimal flight software changes. The paperwill cover the preparation and testing of the new gyroless algorithm, both inground simulations and inflight

Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth

Tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes. One feature of tumor hypoxia is activated expression of carbonic anhydrase IX (CA9), a regulator of pH and tumor growth. In this study, we investigated the hypothesis that impeding the reuptake of bicarbonate produced extracellularly by CA9 could exacerbate the intracellular acidity produced by hypoxic conditions, perhaps compromising cell growth and viability as a result. In 8 of 10 cancer cell lines, we found that hypoxia induced the expression of at least one bicarbonate transporter. The most robust and frequent inductions were of the sodium-driven bicarbonate transporters SLC4A4 and SLC4A9, which rely upon both HIF1α and HIF2α activity for their expression. In cancer cell spheroids, SLC4A4 or SLC4A9 disruption by either genetic or pharmaceutical approaches acidified intracellular pH and reduced cell growth. Furthermore, treatment of spheroids with S0859, a small-molecule inhibitor of sodium-driven bicarbonate transporters, increased apoptosis in the cell lines tested. Finally, RNAi-mediated attenuation of SLC4A9 increased apoptosis in MDA-MB-231 breast cancer spheroids and dramatically reduced growth of MDA-MB-231 breast tumors or U87 gliomas in murine xenografts. Our findings suggest that disrupting pH homeostasis by blocking bicarbonate import might broadly relieve the common resistance of hypoxic tumors to anticancer therapy

DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo.

Resistance to VEGF inhibitors is emerging as a major clinical problem. Notch signaling has been implicated in tumor angiogenesis. Therefore, to investigate mechanisms of resistance to angiogenesis inhibitors, we transduced human glioblastoma cells with retroviruses encoding Notch delta-like ligand 4 (DLL4), grew them as tumor xenografts and then treated the murine hosts with the VEGF-A inhibitor bevacizumab. We found that DLL4-mediated tumor resistance to bevacizumab in vivo. The large vessels induced by DLL4-Notch signaling increased tumor blood supply and were insensitive to bevacizumab. However, blockade of Notch signaling by dibenzazepine, a γ-secretase inhibitor, disrupted the large vessels and abolished the tumor resistance. Multiple molecular mechanisms of resistance were shown, including decreased levels of hypoxia-induced VEGF and increased levels of the VEGF receptor VEGFR1 in the tumor stroma, decreased levels of VEGFR2 in large blood vessels, and reduced levels of VEGFR3 overall. DLL4-expressing tumors were also resistant to a VEGFR targeting multikinase inhibitor. We also observed activation of other pathways of tumor resistance driven by DLL4-Notch signaling, including the FGF2-FGFR and EphB4-EprinB2 pathways, the inhibition of which reversed tumor resistance partially. Taken together, our findings show the importance of classifying mechanisms involved in angiogenesis in tumors, and how combination therapy to block DLL4-Notch signaling may enhance the efficacy of VEGF inhibitors, particularly in DLL4-upregulated tumors, and thus provide a rational base for the development of novel strategies to overcome antiangiogenic resistance in the clinic

Book Reviews

Reviews of the following books: Mainers in the Civil War by Harry Gratwick; The 22nd Maine Volunteer Infantry in the Civil War: A History and Roster by Ned Smith; Write Quick: War and a Woman\u27s Life in Letters 1835-1867 Edited by Ann Fox Chandonnet and Robert Gibson Pevear; Civil War Senator: William Pitt Fessenden and the Fight to Save the American Republic by Robert J. Cook; Lincoln\u27s Friend: Leonard Swett by Robert S. Eckley; We Are in His Hands Whether We Live or Die: The Letters of Brevet Brigadier General Charles Henry Howard edited by David K. Thomson; Fanny & Joshua: The Enigmatic Lives of Frances Caroline Adams and Joshua Lawrence Chamberlain by Diane Monroe Smith; This Birth Place of Souls:The Civil War Nursing Diary of Harriet Eaton edited with an Introduction by Jane E. Schultz; Army at Home: Women and the Civil War on the Northern Home Front by Judith Giesberg; A Visitation of God: Northern Civilians Interpret the Civil War by Sean A. Scott; Freedom National: The Destruction of Slavery in the United States, 1861-1865 by James Oakes; War Upon the Land: Military Strategy and the Transformation of Southern Landscapes during the American Civil War by Lisa M. Brady; Remembering the Civil War: Reunion and the Limits of Reconciliation by Caroline E. Janne

Genome-wide association analysis reveals QTL and candidate mutations involved in white spotting in cattle

International audienceAbstractBackgroundWhite spotting of the coat is a characteristic trait of various domestic species including cattle and other mammals. It is a hallmark of Holstein–Friesian cattle, and several previous studies have detected genetic loci with major effects for white spotting in animals with Holstein–Friesian ancestry. Here, our aim was to better understand the underlying genetic and molecular mechanisms of white spotting, by conducting the largest mapping study for this trait in cattle, to date.ResultsUsing imputed whole-genome sequence data, we conducted a genome-wide association analysis in 2973 mixed-breed cows and bulls. Highly significant quantitative trait loci (QTL) were found on chromosomes 6 and 22, highlighting the well-established coat color genes KIT and MITF as likely responsible for these effects. These results are in broad agreement with previous studies, although we also report a third significant QTL on chromosome 2 that appears to be novel. This signal maps immediately adjacent to the PAX3 gene, which encodes a known transcription factor that controls MITF expression and is the causal locus for white spotting in horses. More detailed examination of these loci revealed a candidate causal mutation in PAX3 (p.Thr424Met), and another candidate mutation (rs209784468) within a conserved element in intron 2 of MITF transcripts expressed in the skin. These analyses also revealed a mechanistic ambiguity at the chromosome 6 locus, where highly dispersed association signals suggested multiple or multiallelic QTL involving KIT and/or other genes in this region.ConclusionsOur findings extend those of previous studies that reported KIT as a likely causal gene for white spotting, and report novel associations between candidate causal mutations in both the MITF and PAX3 genes. The sizes of the effects of these QTL are substantial, and could be used to select animals with darker, or conversely whiter, coats depending on the desired characteristics

Carbonic anhydrase IX promotes tumor growth and necrosis in vivo and inhibition enhances anti-VEGF therapy.

PURPOSE: Bevacizumab, an anti-VEGFA antibody, inhibits the developing vasculature of tumors, but resistance is common. Antiangiogenic therapy induces hypoxia and we observed increased expression of hypoxia-regulated genes, including carbonic anhydrase IX (CAIX), in response to bevacizumab treatment in xenografts. CAIX expression correlates with poor prognosis in most tumor types and with worse outcome in bevacizumab-treated patients with metastatic colorectal cancer, malignant astrocytoma, and recurrent malignant glioma. EXPERIMENTAL DESIGN: We knocked down CAIX expression by short hairpin RNA in a colon cancer (HT29) and a glioblastoma (U87) cell line which have high hypoxic induction of CAIX and overexpressed CAIX in HCT116 cells which has low CAIX. We investigated the effect on growth rate in three-dimensional (3D) culture and in vivo, and examined the effect of CAIX knockdown in combination with bevacizumab. RESULTS: CAIX expression was associated with increased growth rate in spheroids and in vivo. Surprisingly, CAIX expression was associated with increased necrosis and apoptosis in vivo and in vitro. We found that acidity inhibits CAIX activity over the pH range found in tumors (pK = 6.84), and this may be the mechanism whereby excess acid self-limits the build-up of extracellular acid. Expression of another hypoxia inducible CA isoform, CAXII, was upregulated in 3D but not two-dimensional culture in response to CAIX knockdown. CAIX knockdown enhanced the effect of bevacizumab treatment, reducing tumor growth rate in vivo. CONCLUSION: This work provides evidence that inhibition of the hypoxic adaptation to antiangiogenic therapy enhances bevacizumab treatment and highlights the value of developing small molecules or antibodies which inhibit CAIX for combination therapy

Fifteen species in one: deciphering the Brachionus plicatilis species complex (Rotifera, Monogononta) through DNA taxonomy

Understanding patterns and processes in biological diversity is a critical task given current and rapid environmental change. Such knowledge is even more essential when the taxa under consideration are important ecological and evolutionary models. One of these cases is the monogonont rotifer cryptic species complex Brachionus plicatilis, which is by far the most extensively studied group of rotifers, is widely used in aquaculture, and is known to host a large amount of unresolved diversity. Here we collate a dataset of previously available and newly generated sequences of COI and ITS1 for 1273 isolates of the B. plicatilis complex and apply three approaches in DNA taxonomy (i.e. ABGD, PTP, and GMYC) to identify and provide support for the existence of 15 species within the complex. We used these results to explore phylogenetic signal in morphometric and ecological traits, and to understand correlation among the traits using phylogenetic comparative models. Our results support niche conservatism for some traits (e.g. body length) and phylogenetic plasticity for others (e.g. genome size)