Rheb1 is required for mTORC1 and myelination in postnatal brain development

mTor kinase is involved in cell growth, proliferation, and differentiation. The roles of mTor activators, Rheb1 and Rheb2, have not been established in?vivo. Here, we report that Rheb1, but not Rheb2, is critical for embryonic survival and mTORC1 signaling. Embryonic deletion of Rheb1 in neural progenitor cells?abolishes mTORC1 signaling in developing brain and increases mTORC2 signaling. Remarkably, embryonic and early postnatal brain development appears grossly normal in these Rheb1f/f,Nes-cre mice with the notable exception of deficits of myelination. Conditional expression of Rheb1 transgene in neural progenitors increases mTORC1 activity and promotes myelination in the brain. In addition the Rheb1 transgene rescues mTORC1 signaling and hypomyelination in the Rheb1f/f,Nes-cre mice. Our study demonstrates that Rheb1 is essential for mTORC1 signaling and myelination in the brain, and suggests that mTORC1 signaling plays a role in selective cellular adaptations, rather than general cellular viability.     

Characterisation of an engineered trastuzumab IgE antibody and effector cell mechanisms targeting HER2/neu-positive tumour cells

Trastuzumab (Herceptin), a humanized IgG1 antibody raised against the human epidermal growth factor receptor 2 (HER2/neu), is the main antibody in clinical use against breast cancer. Pre-clinical evidence and clinical studies indicate that trastuzumab employs several anti-tumour mechanisms that most likely contribute to enhanced survival of patients with HER2/neu-positive breast carcinomas. New strategies are aimed at improving antibody-based therapeutics like trastuzumab, e.g. by enhancing antibody-mediated effector function mechanisms. Based on our previous findings that a chimaeric ovarian tumour antigen-specific IgE antibody showed greater efficacy in tumour cell killing, compared to the corresponding IgG1 antibody, we have produced an IgE homologue of trastuzumab. Trastuzumab IgE was engineered with the same light- and heavy-chain variable-regions as trastuzumab, but with an epsilon in place of the gamma-1 heavy-chain constant region. We describe the physical characterisation and ligand binding properties of the trastuzumab IgE and elucidate its potential anti-tumour activities in functional assays. Both trastuzumab and trastuzumab IgE can activate monocytic cells to kill tumour cells, but they operate by different mechanisms: trastuzumab functions in antibody-dependent cell-mediated phagocytosis (ADCP), whereas trastuzumab IgE functions in antibody-dependent cell-mediated cytotoxicity (ADCC). Trastuzumab IgE, incubated with mast cells and HER2/neu-expressing tumour cells, triggers mast cell degranulation, recruiting against cancer cells a potent immune response, characteristic of allergic reactions. Finally, in viability assays both antibodies mediate comparable levels of tumour cell growth arrest. These functional characteristics of trastuzumab IgE, some distinct from those of trastuzumab, indicate its potential to complement or improve upon the existing clinical benefits of trastuzumab.     

Salivary peroxidase,Pm, and Ph protein polymorphisms in Malaysians

Summary Three human saliva genetic markers, namely, salivary peroxidase (SAPX), Pm, and Ph proteins, were investigated in the three major ethnic groups of Malaysia: Malays, Chinese, and Indians.For Pm, the allelic frequencies of Pm ⁺ for Malays, Chinese, and Indians are 0.385±0.030, 0.282±0.026, and 0.289±0.026 respectively. For Ph, the allelic frequencies of Ph ⁺ are 0.082±0.016 for Malays, 0.109±0.017 for Chinese, and 0.062±0.013 for Indians. For SAPX, the allelic frequencies of SAPX ¹ in Malays, Chinese, and Indians are 0.762±0.027, 0.755±0.027, and 0.723±0.026 respectively.     

超低能重离子注入作物育种的原初物理机制

从原子核物理学观点出发,采用理论分析与实验测量并举的方法对超级能（〈２００ｋｅｖ）重离子（Ｚ≥６）注入作物（小麦）种子进行诱变育种的原初物理机制进行了研究,结果表明,无论是注入离子本身的射程,还是次级电子,自由基扩散,高温热穗,级联原子和冲击波等次级作用范围都无法触及表皮下面的胚细胞,但注入离子在麦胚内主要元素（Ｃ,Ｎ,Ｏ,Ｓ,Ｐ,Ｋ,Ｃａ）上激发出的特征Ｘ－射线,在其强度减弱为原来的１０＾－３时     

Cardiomyocyte Antihypertrophic Effect of Adipose Tissue Conditioned Medium from Rats and Its Abrogation by Obesity is Mediated by the Leptin to Adiponectin Ratio

White adipocytes are known to function as endocrine organs by secreting a plethora of bioactive adipokines which can regulate cardiac function including the development of hypertrophy. We determined whether adipose tissue conditioned medium (ATCM) generated from the epididymal regions of normal rats can affect the hypertrophic response of cultured rat ventricular myocytes to endothelin-1 (ET-1) administration. Myocytes were treated with ET-1 (10 nM) for 24 hours in the absence or presence of increasing ATCM concentrations. ATCM supressed the hypertrophic response to ET-1 in a concentration-dependent manner, an effect enhanced by the leptin receptor antagonist and attenuated by an antibody against the adiponectin AdipoR1 receptor. Antihypertrophic effects were also observed with ATCM generated from perirenal-derived adipose tissue. However, this effect was absent in ATCM from adipose tissue harvested from corpulent JCR:LA-cp rats. Detailed analyses of adipokine content in ATCM from normal and corpulent rats revealed no differences in the majority of products assayed, although a significant increase in leptin concentrations concomitant with decreased adiponectin levels was observed, resulting in a 11 fold increase in the leptin to adiponectin ratio in ATCM from JCR:LA-cp. The antihypertrophic effect of ATCM was associated with increased phosphorylation of AMP-activated protein kinase (AMPK), an effect abrogated by the AdipoR1 antibody. Moreover, the antihypertrophic effect of ATCM was mimicked by an AMPK activator. There was no effect of ET-1 on mitogen-activated protein kinase (MAPK) activities 24 hour after its addition either in the presence or absence of ATCM. Our study suggests that adipose tissue from healthy subjects exerts antihypertrophic effects via an adiponectin–dependent pathway which is impaired in obesity, most likely due to adipocyte remodelling resulting in enhanced leptin and reduced adiponectin levels.     

A Systematic Review of Hospital-to-School Reintegration Interventions for Children and Youth with Acquired Brain Injury

Objectives

We reviewed the literature on interventions that aimed to improve hospital-to-school reintegration for children and youth with acquired brain injury (ABI). ABI is the leading cause of disability among children and youth. A successful hospital-to-school reintegration process is essential to the rehabilitative process. However, little is known about the effective components of of such interventions.

Methods and findings

Our research team conducted a systematic review, completing comprehensive searches of seven databases and selected reference lists for relevant articles published in a peer-reviewed journal between 1989 and June 2014. We selected articles for inclusion that report on studies involving: a clinical population with ABI; sample had an average age of 20 years or younger; an intentional structured intervention affecting hospital-to-school transitions or related components; an experimental design; and a statistically evaluated health outcome. Two independent reviewers applied our inclusion criteria, extracted data, and rated study quality. A meta-analysis was not feasible due to the heterogeneity of the studies reported. Of the 6933 articles identified in our initial search, 17 articles (reporting on 350 preadolescents and adolescents, aged 4–19, (average age 11.5 years, SD: 2.21) met our inclusion criteria. They reported on interventions varying in number of sessions (one to 119) and session length (20 minutes to 4 hours). The majority of interventions involved multiple one-to-one sessions conducted by a trained clinician or educator, homework activities, and parental involvement. The interventions were delivered through different settings and media, including hospitals, schools, and online. Although outcomes varied (with effect sizes ranging from small to large), 14 of the articles reported at least one significant improvement in cognitive, social, psychological, or behavioral functioning or knowledge of ABI.

Conclusions

Cognitive, behavioral, and problem-solving interventions have the potential to improve school reintegration for youth with ABI. However, more comprehensive interventions are needed to help link rehabilitation clinicians, educators, adolescents, and families.     

Crystal structure of recombinant trypsin-solubilized fragment of cytochrome b(5) and the structural comparison with Val61His mutant

The crystal structure of the recombinant trypsin-solubilized fragment of the microsomal cytochrome b(5) from bovine liver has been determined at 1.9 A resolution and compared with the reported crystal structure of the lipase-solubilized fragment of the membrane protein cytochrome b(5). The two structures are similar to each other. However, some detailed structural differences are observed: the conformation of the segment Asn16-Ser20 is quite different, some helices around the heme and some segments between the helices are shifted slightly, the heme is rotated about the normal of the mean plane of heme, one of the propionates of the heme exhibits a different conformation. The average coordination distances between the iron and the two nitrogen atoms of the imidazole ligands are the same in the two structures. Most of the structural differences can be attributed to the different intermolecular interactions which result from the crystal packing. The wild-type protein structure is also compared with its Val61His mutant, showing that the heme binding and the main chain conformations are basically identical with each other except for the local area of the mutation site. However, when Val61 is mutated to histidine, the large side chain of His61 is forced to point away from the heme pocket toward the solvent region, disturbing the micro-environment of the heme pocket and influencing the stability and the redox potential of the protein.     

UVB-based mate-choice cues used by females of the jumping spider Phintella vittata

Although there are numerous examples of animals having photoreceptors sensitive to UVA (315-400 nm) [1] and relying on UVA-based mate-choice cues [2-5], here we provide the first evidence of an animal using UVB (280-315 nm) for intraspecific communication. An earlier study showed that Phintella vittata, a jumping spider (Salticidae) from China, reflects UVB [6]. By performing six series of binary mate-choice experiments in which we varied lighting conditions with filters (UVB+ [no filter] versus UVB-, UVB+ versus ND1, UVB+ versus ND2, UVB- versus ND1, UVB- versus ND2, and UVB- versus UVA-), we show that significantly more UVB + males than UVB- males are chosen by females as preferred mates. Female preference for UVB-reflective males is not affected by differences in brightness or by UVA.