Assessment of Breast Cancer Risk Based on Mammary Gland Volume Measured with CT

We investigated the relationship between mammary gland volume (MGV) of the breast as measured with three-dimensional chest computed tomography (CT) and breast cancer risk. Univariate analysis was used to assess the relationship between MGV and known risk factors in 427 healthy women. A case control study (97 cases and 194 controls) was conducted to assess breast cancer risk. MGV was significantly smaller for postmenopausal women than for premenopausal women, and was significantly larger for women with a family history of breast cancer than for women without. MGV, body mass index (BMI), and rate of family history of breast cancer were significantly higher among breast cancer patients than among healthy women, and number of deliveries was significantly lower among breast cancer patients. In postmenopausal women, age at menarche was significantly younger for breast cancer patients. MGV correlated well with breast cancer risk factors. The highest odds ratio was 4.9 for premenopausal women with the largest MGV. Regardless of menopausal status, the greater the MGV, the higher the odds ratio. Our results constitute the first reliable data on the relationship between MGV and breast cancer obtained through exact volume analysis

The thyroid function of Graves' disease patients is aggravated by depressive personality during antithyroid drug treatment

<p>Abstract</p> <p>Background</p> <p>We previously reported that depressive personality (the scores of hypochondriasis, depression and psychasthenia determined by the Minnesota Multiphasic Personality Inventory (MMPI)) and daily hassles of Graves' disease (GD) patients treated long trem with antithyroid drug (ATD) were significantly higher in a relapsed group than in a remitted group, even in the euthyroid state. The present study aims to examine the relationship among depressive personality, emotional stresses, thyroid function and the prognosis of hyperthyroidism in newly diagnosed GD patients.</p> <p>Methods</p> <p>Sixty-four untreated GD patients responded to the MMPI for personality traits, the Natsume's Stress Inventory for major life events, and the Hayashi's Daily Life Stress Inventory for daily life stresses before and during ATD treatment.</p> <p>Results</p> <p>In the untreated thyrotoxic state, depressive personality (T-scores of hypochondriasis, depression or psychasthenia greater than 60 points in MMPI) were found for 44 patients (69%). For 15 (23%) of these patients, the scores decreased to the normal range after treatment. However, depressive personality persisted after treatment in the remaining 29 patients (46%). Normal scores before treatment were found for 20 patients (31%), and the scores were persistently normal for 15 patients (23%). The remaining 5 patients (8%) had higher depressive personality after treatment. Such depressive personality was not associated with the severity of hyperthyroidism. Serum TSH receptor antibody activity at three years after treatment was significantly (p = 0.0351) greater in the depression group than in the non- depression group. The remission rate at four years after treatment was significantly (p = 0.0305) lower in the depression group than in the non- depression group (22% vs 52%).</p> <p>Conclusion</p> <p>The data indicate that in GD patients treated with ATD, depressive personality during treatment reflects the effect of emotional stress more than that of thyrotoxicosis and that it aggravates hyperthyroidism. Psychosomatic therapeutic approaches including antipsychiatric drugs and/or psychotherapy appears to be useful for improving the prognosis of hyperthyroidism.</p

Discretized Wiener-Khinchin theorem for Fourier-Laplace transformation: application to molecular simulations

The Wiener-Khinchin theorem for the Fourier-Laplace transformation (WKT-FLT) provides a robust method to calculate numerically single-side Fourier transforms of arbitrary autocorrelation functions from molecular simulations. However, the existing WKT-FLT equation produces two artifacts in the output of the frequency-domain relaxation function. In addition, these artifacts are more apparent in the frequency-domain response function converted from the relaxation function. We find the sources of these artifacts that are associated with the discretization of the WKT-FLT equation. Taking these sources into account, we derive the new discretized WKT-FLT equations designated for both the frequency-domain relaxation and response functions with the artifacts removed. The use of the discretized WKT-FLT equations is illustrated by a flow chart of an on-the-fly algorithm. We also give application examples of the discretized WKT-FLT equations for computing dynamic structure factor and wave-vector-dependent dynamic susceptibility from molecular simulations

Emerging Evidence of Translational Control by AU-Rich Element-Binding Proteins

RNA-binding proteins (RBPs) are key regulators of posttranscriptional gene expression and control many important biological processes including cell proliferation, development, and differentiation. RBPs bind specific motifs in their target mRNAs and regulate mRNA fate at many steps. The AU-rich element (ARE) is one of the major cis-regulatory elements in the 3′ untranslated region (UTR) of labile mRNAs. Many of these encode factors requiring very tight regulation, such as inflammatory cytokines and growth factors. Disruption in the control of these factors’ expression can cause autoimmune diseases, developmental disorders, or cancers. Therefore, these mRNAs are strictly regulated by various RBPs, particularly ARE-binding proteins (ARE-BPs). To regulate mRNA metabolism, ARE-BPs bind target mRNAs and affect some factors on mRNAs directly, or recruit effectors, such as mRNA decay machinery and protein kinases to target mRNAs. Importantly, some ARE-BPs have stabilizing roles, whereas others are destabilizing, and ARE-BPs appear to compete with each other when binding to target mRNAs. The function of specific ARE-BPs is modulated by posttranslational modifications (PTMs) including methylation and phosphorylation, thereby providing a means for cellular signaling pathways to regulate stability of specific target mRNAs. In this review, we summarize recent studies which have revealed detailed molecular mechanisms of ARE-BP-mediated regulation of gene expression and also report on the importance of ARE-BP function in specific physiological contexts and how this relates to disease. We also propose an mRNP regulatory network based on competition between stabilizing ARE-BPs and destabilizing ARE-BPs

A molecular dynamics simulation of polymer crystallization from oriented amorphous state

Molecular process of crystallization from an oriented amorphous state was reproduced by molecular dynamics simulation for a realistic polyethylene model. Initial oriented amorphous state was obtained by uniaxial drawing an isotropic glassy state at 100 K. By the temperature jump from 100 K to 330 K, there occurred the crystallization into the fiber structure, during the process of which we observed the developments of various order parameters. The real space image and its Fourier transform revealed that a hexagonally ordered domain was initially formed, and then highly ordered crystalline state with stacked lamellae developed after further adjustment of the relative heights of the chains along their axes.Comment: 4 pages, 3 figure

Regulation of CCR4-NOT complex deadenylase activity and cellular responses by MK2-dependent phosphorylation of CNOT2

CCR4-NOT complex-mediated mRNA deadenylation serves critical functions in multiple biological processes, yet how this activity is regulated is not fully understood. Here, we show that osmotic stress induces MAPKAPK-2 (MK2)-mediated phosphorylation of CNOT2. Programmed cell death is greatly enhanced by osmotic stress in CNOT2-depleted cells, indicating that CNOT2 is responsible for stress resistance of cells. Although wild-type (WT) and non-phosphorylatable CNOT2 mutants reverse this sensitivity, a phosphomimetic form of CNOT2, in which serine at the phosphorylation site is replaced with glutamate, does not have this function. We also show that mRNAs have elongated poly(A) tails in CNOT2-depleted cells and that introduction of CNOT2 WT or a non-phosphorylatable mutant, but not phosphomimetic CNOT2, renders their poly(A) tail lengths comparable to those in control HeLa cells. Consistent with this, the CCR4-NOT complex containing phosphomimetic CNOT2 exhibits less deadenylase activity than that containing CNOT2 WT. These data suggest that CCR4-NOT complex deadenylase activity is regulated by post-translational modification, yielding dynamic control of mRNA deadenylation

ARE-binding protein ZFP36L1 interacts with CNOT1 to directly repress translation via a deadenylation-independent mechanism

Eukaryotic gene expression can be spatiotemporally tuned at the post-transcriptional level by cis-regulatory elements in mRNA sequences. An important example is the AU-rich element (ARE), which induces mRNA destabilization in a variety of biological contexts in mammals and can also mediate translational control. Regulation is mediated by trans-acting factors that recognize the ARE, such as Tristetraprolin (TTP) and BRF1/ZFP36L1. Although both proteins can destabilize their target mRNAs through the recruitment of the CCR4-NOT deadenylation complex, TTP also directly regulates translation. Whether ZFP36L1 can directly repress translation remains unknown. Here, we used an in vitro translation system derived from mammalian cell lines to address this key mechanistic issue in ARE regulation by ZFP36L1. Functional assays with mutant proteins reveal that ZFP36L1 can repress translation via AU-Rich elements independent of deadenylation. ZFP36L1-mediated translation repression requires interaction between ZFP36L1 and CNOT1, suggesting that it might use a repression mechanism similar to either TPP or miRISC. However, several lines of evidence suggest that the similarity ends there. Unlike, TTP, it does not efficiently interact with either 4E-HP or GIGYF2, suggesting it does not repress translation by recruiting these proteins to the mRNA cap. Moreover, ZFP36L1 could not repress ECMV-IRES driven translation and was resistant to pharmacological eIF4A inhibitor silvestrol, suggesting fundamental differences with miRISC repression via eIF4A. Collectively, our results reveal that ZFP36L1 represses translation directly and suggest that it does so via a novel mechanism distinct from other translational regulators that interact with the CCR4-NOT deadenylase complex

Mechanisms of translational regulation by a human eIF5-mimic protein

The translation factor eIF5 is an important partner of eIF2, directly modulating its function in several critical steps. First, eIF5 binds eIF2/GTP/Met-tRNAiMet ternary complex (TC), promoting its recruitment to 40S ribosomal subunits. Secondly, its GTPase activating function promotes eIF2 dissociation for ribosomal subunit joining. Finally, eIF5 GDP dissociation inhibition (GDI) activity can antagonize eIF2 reactivation by competing with the eIF2 guanine exchange factor (GEF), eIF2B. The C-terminal domain (CTD) of eIF5, a W2-type HEAT domain, mediates its interaction with eIF2. Here, we characterize a related human protein containing MA3- and W2-type HEAT domains, previously termed BZW2 and renamed here as eIF5-mimic protein 1 (5MP1). Human 5MP1 interacts with eIF2 and eIF3 and inhibits general and gene-specific translation in mammalian systems. We further test whether 5MP1 is a mimic or competitor of the GEF catalytic subunit eIF2Bε or eIF5, using yeast as a model. Our results suggest that 5MP1 interacts with yeast eIF2 and promotes TC formation, but inhibits TC binding to the ribosome. Moreover, 5MP1 is not a GEF but a weak GDI for yeast eIF2. We propose that 5MP1 is a partial mimic and competitor of eIF5, interfering with the key steps by which eIF5 regulates eIF2 function

Drop out from out-patient mental healthcare in the World Health Organization's World Mental Health Survey initiative

Funding information: ... The Portuguese Mental Health Study was carried out by the Department of Mental Health, Faculty of Medical Sciences, NOVA University of Lisbon, with collaboration of the Portuguese Catholic University, and was funded by Champalimaud Foundation, Gulbenkian Foundation, Foundation for Science and Technology (FCT) and Ministry of Health...Background: Previous community surveys of the drop out from mental health treatment have been carried out only in the USA and Canada. Aims: To explore mental health treatment drop out in the World Health Organization World Mental Health Surveys. Method: Representative face-to-face household surveys were conducted among adults in 24 countries. People who reported mental health treatment in the 12 months before interview (n = 8482) were asked about drop out, defined as stopping treatment before the provider wanted. Results: Overall, drop out was 31.7%: 26.3% in high-income countries, 45.1% in upper-middle-income countries, and 37.6% in low/ lower-middle-income countries. Drop out from psychiatrists was 21.3% overall and similar across country income groups (high 20.3%, upper-middle 23.6%, low/lower-middle 23.8%) but the pattern of drop out across other sectors differed by country income group. Drop out was more likely early in treatment, particularly after the second visit. Conclusions: Drop out needs to be reduced to ensure effective treatment.publishersversionpublishe