An allosteric regulator of R7-RGS proteins influences light-evoked activity and glutamatergic waves in the inner retina

In the outer retina, G protein-coupled receptor (GPCR) signaling mediates phototransduction and synaptic transmission between photoreceptors and ON bipolar cells. In contrast, the functions of modulatory GPCR signaling networks in the inner retina are less well understood. We addressed this question by determining the consequences of augmenting modulatory Gi/o signaling driven by endogenous transmitters. This was done by analyzing the effects of genetically ablating the R7 RGS-binding protein (R7BP), a membrane-targeting protein and positive allosteric modulator of R7-RGS (regulator of the G protein signaling 7) family that deactivates Gi/oα subunits. We found that R7BP is expressed highly in starburst amacrine cells and retinal ganglion cells (RGCs). As indicated by electroretinography and multielectrode array recordings of adult retina, ablation of R7BP preserved outer retina function, but altered the firing rate and latency of ON RGCs driven by rods and cones but not rods alone. In developing retina, R7BP ablation increased the burst duration of glutamatergic waves whereas cholinergic waves were unaffected. This effect on glutamatergic waves did not result in impaired segregation of RGC projections to eye-specific domains of the dorsal lateral geniculate nucleus. R7BP knockout mice exhibited normal spatial contrast sensitivity and visual acuity as assessed by optomotor reflexes. Taken together these findings indicate that R7BP-dependent regulation of R7-RGS proteins shapes specific aspects of light-evoked and spontaneous activity of RGCs in mature and developing retina

The CBM-opathies—A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex

The caspase recruitment domain family member 11 (CARD11 or CARMA1)—B cell CLL/lymphoma 10 (BCL10)—MALT1 paracaspase (MALT1) [CBM] signalosome complex serves as a molecular bridge between cell surface antigen receptor signaling and the activation of the NF-κB, JNK, and mTORC1 signaling axes. This positions the CBM complex as a critical regulator of lymphocyte activation, proliferation, survival, and metabolism. Inborn errors in each of the CBM components have now been linked to a diverse group of human primary immunodeficiency diseases termed “CBM-opathies.” Clinical manifestations range from severe combined immunodeficiency to selective B cell lymphocytosis, atopic disease, and specific humoral defects. This surprisingly broad spectrum of phenotypes underscores the importance of “tuning” CBM signaling to preserve immune homeostasis. Here, we review the distinct clinical and immunological phenotypes associated with human CBM complex mutations and introduce new avenues for targeted therapeutic intervention

The role of parental investments for cognitive and noncognitive skill formation : evidence for the first 11 years of life

This paper examines the impact of parental investments on the development of cognitive, mental and emotional skills during childhood using data from a longitudinal study, the Mannheim Study of Children at Risk, starting at birth. Our work offers three important innovations. First, we use reliable measures of the child’s cognitive, mental and emotional skills as well as accurate measures of parental investment. Second, we estimate latent factor models to account for unobserved characteristics of children. Third, we examine the skill development for girls and boys separately, as well as for children who were born with either organic or psychosocial risk. We find a decreasing impact of parental investments on cognitive and mental skills, while emotional skills seem to be unaffected by parental investment throughout childhood. Thus, initial inequality persists during childhood. Since families are the main sources of education during the first years of life, our results have important implications for the quality of the parent-child relationship

hMMS2 serves a redundant role in human PCNA polyubiquitination

<p>Abstract</p> <p>Background</p> <p>In yeast, DNA damage leads to the mono and polyubiquitination of the sliding clamp PCNA. Monoubiquitination of PCNA is controlled by RAD18 (E3 ligase) and RAD6 (E2 conjugating enzyme), while the extension of the monoubiquitinated PCNA into a polyubiquitinated substrate is governed by RAD5, and the heterodimer of UBC13/MMS2. Each modification directs a different branch of the DNA damage tolerance pathway (DDT). While PCNA monoubiquitination leads to error-prone bypass via TLS, biochemical studies have identified MMS2 along with its heteromeric partner UBC13 to govern the error-free repair of DNA lesions by catalyzing the formation of lysine 63-linked polyubiquitin chains (K63-polyUb). Recently, it was shown that PCNA polyubiquitination is conserved in human cells and that this modification is dependent on RAD18, UBC13 and SHPRH. However, the role of hMMS2 in this process was not specifically addressed.</p> <p>Results</p> <p>In this report we show that mammalian cells in which MMS2 was reduced by siRNA-mediated knockdown maintains PCNA polyubiquitination while a knockdown of RAD18 or UBC13 abrogates PCNA ubiquitination. Moreover, the additional knockdown of a UEV1A (MMS2 homolog) does not deplete PCNA polyubiquitination. Finally, mouse embryonic stem cells null for MMS2 with or without the additional depletion of mUEV1A continue to polyubiquitinated PCNA with normal kinetics.</p> <p>Conclusion</p> <p>Our results point to a high level of redundancy in the DDT pathway and suggest the existence of another hMMS2 variant (hMMSv) or complex that can compensate for its loss.</p

Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours

The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named ‘Immunoscore’ has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune). © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

A Study On The Model Of Profit And Risk In Xiamen’s Commercial Banks

随着相对滞后的金融体制改革提上议事日程，金融业中的银行业的风险和效益的矛盾对立统一日益成为讨论的焦点、热点。加入WTO对金融业意味着拥有先进管理技术和经验的外资银行抢滩国内银行业务，其对国内中资银行的竞争和生存环境的影响是巨大且不可预测的。作者认为国内中资银行是缺乏效率的，为避免银行命脉被外资控制，国内中资银行不能讳疾忌医，而要以有容乃大、自省的态度积极寻求市场经济下的解决之道，最可取的莫过于解剖一只麻雀。 按照这一思路，本文选取了厦门8家经营较稳定的商业银行进行收益风险模式比较，为国内其他中资商业银行的经营管理提供实证参考。 第一章导言。对银行经营活动的一般特点进行描述。提出银行作为经济...Owing to the combination between banking and economics , influencing factor is increasingly complicated. Banker needs to design one macroanalysis model to logically judge different kinds of income chance and danger all banks faced with，through which banker may supply effective diagnose for banking operating management. The theses takes banking 'data in Xiamen as an example .It exists that huge c...学位：工商管理硕士院系专业：管理学院工商管理教育中心_工商管理硕士(MBA)学号：19981505

Complications and pitfalls of lumbar interlaminar and transforaminal epidural injections

Lumbar interlaminar and transforaminal epidural injections are used in the treatment of lumbar radicular pain and other lumbar spinal pain syndromes. Complications from these procedures arise from needle placement and the administration of medication. Potential risks include infection, hematoma, intravascular injection of medication, direct nerve trauma, subdural injection of medication, air embolism, disc entry, urinary retention, radiation exposure, and hypersensitivity reactions. The objective of this article is to review the complications of lumbar interlaminar and transforaminal epidural injections and discuss the potential pitfalls related to these procedures. We performed a comprehensive literature review through a Medline search for relevant case reports, clinical trials, and review articles. Complications from lumbar epidural injections are extremely rare. Most if not all complications can be avoided by careful technique with accurate needle placement, sterile precautions, and a thorough understanding of the relevant anatomy and contrast patterns on fluoroscopic imaging