Neuroligin-3: A Circuit-Specific Synapse Organizer That Shapes Normal Function and Autism Spectrum Disorder-Associated Dysfunction

Chemical synapses provide a vital foundation for neuron-neuron communication and overall brain function. By tethering closely apposed molecular machinery for presynaptic neurotransmitter release and postsynaptic signal transduction, circuit- and context- specific synaptic properties can drive neuronal computations for animal behavior. Trans-synaptic signaling via synaptic cell adhesion molecules (CAMs) serves as a promising mechanism to generate the molecular diversity of chemical synapses. Neuroligins (Nlgns) were discovered as postsynaptic CAMs that can bind to presynaptic CAMs like Neurexins (Nrxns) at the synaptic cleft. Among the four (Nlgn1-4) or five (Nlgn1-3, Nlgn4X, and Nlgn4Y) isoforms in rodents or humans, respectively, Nlgn3 has a heterogeneous expression and function at particular subsets of chemical synapses and strong association with non-syndromic autism spectrum disorder (ASD). Several lines of evidence have suggested that the unique expression and function of Nlgn3 protein underlie circuit-specific dysfunction characteristic of non-syndromic ASD caused by the disruption of Nlgn3 gene. Furthermore, recent studies have uncovered the molecular mechanism underlying input cell-dependent expression of Nlgn3 protein at hippocampal inhibitory synapses, in which trans-synaptic signaling of specific alternatively spliced isoforms of Nlgn3 and Nrxn plays a critical role. In this review article, we overview the molecular, anatomical, and physiological knowledge about Nlgn3, focusing on the circuit-specific function of mammalian Nlgn3 and its underlying molecular mechanism. This will provide not only new insight into specific Nlgn3-mediated trans-synaptic interactions as molecular codes for synapse specification but also a better understanding of the pathophysiological basis for non-syndromic ASD associated with functional impairment in Nlgn3 gene

Laser spectroscopy of iridium monoboride

High resolution laser induced fluorescence spectrum of IrB in the spectral region between 545 and 610 nm has been recorded and analyzed. Reacting laser-ablated iridium atoms with 1% B2 H6 seeded in argon produced the IrB molecule. This is the first experimental observation of the IrB molecule. Four vibronic transition bands, (v,0) with v=0-3 of an electronic transition system, have been observed. Spectra of all four isotopic molecules, Ir191 B10, Ir193 B10, Ir191 B11, and Ir193 B11, were recorded. Isotopic relationships confirmed the carrier of the spectra and the vibrational quantum number assignment. Preliminary analysis of rotational lines showed that these vibronic bands are with ′ =2 and ″ =3. The electronic transition identified is assigned as the [16.5] Π23 -X Δ33 system. Partially resolved hyperfine structure which conforms to the Hund's case aΒ coupling scheme has been observed and analyzed. The bond length r0 of the lower X Δ33 state of IrB was determined to be 1.7675 Å. © 2008 American Institute of Physics.published_or_final_versio

Direct health care costs of treating seasonal affective disorder: a comparison of light therapy and fluoxetine.

Objective. To compare the direct mental health care costs between individuals with Seasonal Affective Disorder randomized to either fluoxetine or light therapy. Methods. Data from the CANSAD study was used. CANSAD was an 8-week multicentre double-blind study that randomized participants to receive either light therapy plus placebo capsules or placebo light therapy plus fluoxetine. Participants were aged 18-65 who met criteria for major depressive episodes with a seasonal (winter) pattern. Mental health care service use was collected for each subject for 4 weeks prior to the start of treatment and for 4 weeks prior to the end of treatment. All direct mental health care services costs were analysed, including inpatient and outpatient services, investigations, and medications. Results. The difference in mental health costs was significantly higher after treatment for the light therapy group compared to the medication group-a difference of $111.25 (z = -3.77, P = 0.000). However, when the amortized cost of the light box was taken into the account, the groups were switched with the fluoxetine group incurring greater direct care costs-a difference of$75.41 (z = -2.635, P = 0.008). Conclusion. The results suggest that individuals treated with medication had significantly less mental health care cost after-treatment compared to those treated with light therapy

Workplace sexual harassment : exploring the experience of tour leaders in an Asian context

Workplace sexual harassment is an issue that has gained increasing prominence in recent years. Owing to factors such as long working hours, night shifts, the prevalence of alcohol and the intimacy of “hospitality service”, the hospitality/tourism industry is particularly susceptible to the problem of sexual harassment (Davis, 1998; Poulston, 2008b; Yagil, 2008). Sexual harassment can have numerous negative effects, including poor working relationships, monetary loss (Gutek, 1985; Schneider et al., 1997), employee dissatisfaction, loss of attachment to the organisation (Boyd, 2002; Gettman & Gelfand, 2007) and increased employee turnover intentions (Burke, 1995; Laband & Lentz, 1998). At an organisational level, high turnover and labour costs are recognised human resource management challenges in the hospitality/tourism industry and, therefore, it is critical for the industry to pay attention to the problem of sexual harassment. However, protecting associates from unwanted sexual attention, whether from colleagues, managers or customers, is also about an employer’s duty of care for their staff and touches on a range of associated equal opportunities and wider ethical concerns (Goldsmith et al., 1997).The purpose of the study is to investigate sexual harassment among tour leaders in Taiwan. The research objectives of this study are as follows:1.To investigate tour leaders’ experiences of sexual harassment behavior at work; 2.To investigate tour leaders’ awareness of the organisational policies/regulations relating to sexual harassment in the workplace

IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline

Alzheimer’s disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD

Developing the host for targeted integration cell line development

Unlike the conventional random integration (RI) cell line development (CLD), the targeted integration (TI) CLD introduces the transgene at a predetermined “hot-spot” in the CHO genome with a defined copy number (1-2 copies). Given the low copy number and the pretested integration site, TI cell lines likely exhibit better stability compared to RI cell lines. In this study, we performed a genome wide screening using transposon based cassette integration and established a TI host (255-3) that has a single landing cassette inserted in its genome. Host 255-3 was able to support the CLD for three test molecules with product titers similar to those of the corresponding RI cell lines. For two regular antibody test cases, the top four TI cell lines achieved ~4-5g/L. For a proven difficult to express antibody, the top four TI lines achieved ~1-1.2g/L. The product titer for this hard to express molecule was increased 3-fold with additional vector improvement. Moreover, the timeline for CLD was shortened by ~2 weeks and resources required per cell line were substantially reduced using the TI method. Together these data indicate that the TI host we developed can be a suitable host to support our clinical / commercial CLD

Selective Over-Expression of Endothelin-1 in Endothelial Cells Exacerbates Inner Retinal Edema and Neuronal Death in Ischemic Retina

The level of endothelin-1 (ET-1), a potent vasoconstrictor, was associated with retinopathy under ischemia. The effects of endothelial endothelin-1 (ET-1) over-expression in a transgenic mouse model using Tie-1 promoter (TET-1 mice) on pathophysiological changes of retinal ischemia were investigated by intraluminal insertion of a microfilament up to middle cerebral artery (MCA) to transiently block the ophthalmic artery. Two-hour occlusion and twenty-two-hour reperfusion were performed in homozygous (Hm) TET-1 mice and their non-transgenic (NTg) littermates. Presence of pyknotic nuclei in ganglion cell layer (GCL) was investigated in paraffin sections of ipsilateral (ischemic) and contralateral (non-ischemic) retinae, followed by measurement of the thickness of inner retinal layer. Moreover, immunocytochemistry of glial fibrillary acidic protein (GFAP), glutamine synthetase (GS) and aquaporin-4 (AQP4) peptides on retinal sections were performed to study glial cell reactivity, glutamate metabolism and water accumulation, respectively after retinal ischemia. Similar morphology was observed in the contralateral retinae of NTg and Hm TET-1 mice, whereas ipsilateral retina of NTg mice showed slight structural and cellular changes compared with the corresponding contralateral retina. Ipsilateral retinae of Hm TET-1 mice showed more significant changes when compared with ipsilateral retina of NTg mice, including more prominent cell death in GCL characterized by the presence of pyknotic nuclei, elevated GS immunoreactivity in Müller cell bodies and processes, increased AQP-4 immunoreactivity in Müller cell processes, and increased inner retinal thickness. Thus, over-expression of endothelial ET-1 in TET-1 mice may contribute to increased glutamate-induced neurotoxicity on neuronal cells and water accumulation in inner retina leading to edema