Pathological progression induced by the frontotemporal dementia-associated R406W tau mutation in patient-derived iPSCs

Mutations in the microtubule-associated protein tau (MAPT) gene are known to cause familial frontotemporal dementia (FTD). The R406W tau mutation is a unique missense mutation whose patients have been reported to exhibit Alzheimer\u27s disease (AD)-like phenotypes rather than the more typical FTD phenotypes. In this study, we established patient-derived induced pluripotent stem cell (iPSC) models to investigate the disease pathology induced by the R406W mutation. We generated iPSCs from patients and established isogenic lines using CRISPR/Cas9. The iPSCs were induced into cerebral organoids, which were dissociated into cortical neurons with high purity. In this neuronal culture, the mutant tau protein exhibited reduced phosphorylation levels and was increasingly fragmented by calpain. Furthermore, the mutant tau protein was mislocalized and the axons of the patient-derived neurons displayed morphological and functional abnormalities, which were rescued by microtubule stabilization. The findings of our study provide mechanistic insight into tau pathology and a potential for therapeutic intervention

A Pilot Study: The Beneficial Effects of Combined Statin-exercise Therapy on Cognitive Function in Patients with Coronary Artery Disease and Mild Cognitive Decline.

Objective Hypercholesterolemia, a risk factor in cognitive impairment, can be treated with statins. However, cognitive decline associated with "statins" (HMG-CoA reductase inhibitors) is a clinical concern. This pilot study investigated the effects of combining statins and regular exercise on cognitive function in coronary artery disease (CAD) patients with prior mild cognitive decline. Methods We recruited 43 consecutive CAD patients with mild cognitive decline. These patients were treated with a statin and weekly in-hospital aerobic exercise for 5 months. We measured serum lipids, exercise capacity, and cognitive function using the mini mental state examination (MMSE). Results Low-density lipoprotein cholesterol levels were significantly decreased, and maximum exercise capacity (workload) was significantly increased in patients with CAD and mild cognitive decline after treatment compared with before. Combined statin-exercise therapy significantly increased the median (range) MMSE score from 24 (22-25) to 25 (23-27) across the cohort (p<0.01). Changes in body mass index (BMI) were significantly and negatively correlated with changes in the MMSE. After treatment, MMSE scores in the subgroup of patients that showed a decrease in BMI were significantly improved, but not in the BMI-increased subgroup. Furthermore, the patients already on a statin at the beginning of the trial displayed a more significant improvement in MMSE score than statin-naïve patients, implying that exercise might be the beneficial aspect of this intervention as regards cognition. In a multivariate logistic regression analysis adjusted for age >65 years, sex, and presence of diabetes mellitus, a decrease in BMI during statin-exercise therapy was significantly correlated with an increase in the MMSE score (odds ratio: 4.57, 95% confidence interval: 1.05-20.0; p<0.05). Conclusion Statin-exercise therapy may help improve cognitive dysfunction in patients with CAD and pre-existing mild cognitive decline

The critical behavior of 3D Ising glass models: universality and scaling corrections

We perform high-statistics Monte Carlo simulations of three three-dimensional Ising spin-glass models: the +-J Ising model for two values of the disorder parameter p, p=1/2 and p=0.7, and the bond-diluted +-J model for bond-occupation probability p_b = 0.45. A finite-size scaling analysis of the quartic cumulants at the critical point shows conclusively that these models belong to the same universality class and allows us to estimate the scaling-correction exponent omega related to the leading irrelevant operator, omega=1.0(1). We also determine the critical exponents nu and eta. Taking into account the scaling corrections, we obtain nu=2.53(8) and eta=-0.384(9).Comment: 9 pages, published versio

Analysis of Medaka sox9 Orthologue Reveals a Conserved Role in Germ Cell Maintenance

The sex determining gene is divergent among different animal species. However, sox9 is up-regulated in the male gonads in a number of species in which it is the essential regulator of testis determination. It is therefore often discussed that the sex determining gene-sox9 axis functions in several vertebrates. In our current study, we show that sox9b in the medaka (Oryzias latipes) is one of the orthologues of mammalian Sox9 at syntenic and expression levels. Medaka sox9b affects the organization of extracellular matrices, which represents a conserved role of sox9, but does not directly regulate testis determination. We made this determination via gene expression and phenotype analyses of medaka with different copy numbers of sox9b. Sox9b is involved in promoting cellular associations and is indispensible for the proper proliferation and survival of germ cells in both female and male medaka gonads. Medaka mutants that lack sox9b function exhibit a seemingly paradoxical phenotype of sex reversal to male. This is explained by a reduction in the germ cell number associated with aberrant extracellular matrices. Together with its identified roles in other vertebrate gonads, a testis-determining role for Sox9 in mammals is likely to have been neofunctionalized and appended to its conserved role in germ cell maintenance

Essential pre-treatment imaging examinations in patients with endoscopically-diagnosed early gastric cancer

<p>Abstract</p> <p>Background</p> <p>There have been no reports discussing which imaging procedures are truly necessary before treatment of endoscopically-diagnosed early gastric cancer (eEGC). The aim of this pilot study was to show which imaging examinations are essential to select indicated treatment or appropriate strategy in patients with eEGC.</p> <p>Methods</p> <p>In 140 consecutive patients (95 men, 45 women; age, 66.4 +/- 11.3 years [mean +/- standard deviation], range, 33-90) with eEGC which were diagnosed during two years, the pre-treatment results of ultrasonography (US) and contrast-enhanced computed tomography (CT) of the abdomen, barium enema (BE) and chest radiography (CR) were retrospectively reviewed. Useful findings that might affect indication or strategy were evaluated.</p> <p>Results</p> <p>US demonstrated useful findings in 13 of 140 patients (9.3%): biliary tract stones (n = 11) and other malignant tumors (n = 2). Only one useful finding was demonstrated on CT (pancreatic intraductal papillary mucinous tumor) but not on US (0.7%; 95% confidential interval [CI], 2.1%). BE demonstrated colorectal carcinomas in six patients and polyps in 10 patients, altering treatment strategy (11.4%; 95%CI, 6.1-16.7%). Of these, only two colorectal carcinomas were detected on CT. CR showed three relevant findings (2.1%): pulmonary carcinoma (n = 1) and cardiomegaly (n = 2). Seventy-nine patients (56%) were treated surgically and 56 patients were treated by endoscopic intervention. The remaining five patients received no treatment due to various reasons.</p> <p>Conclusions</p> <p>US, BE and CR may be essential as pre-treatment imaging examinations because they occasionally detect findings which affect treatment indication and strategy, although abdominal contrast-enhanced CT rarely provide additional information.</p

Rapid synthesis and enhancement in down conversion emission properties of BaAl2O4:Eu2+,RE3+ (RE3+=Y, Pr) nanophosphors

[EN] BaAl2O4:Eu2+,RE3+ (RE3+=Y, Pr) down conversion nanophosphors were prepared at 600 °C by a rapid gel combustion technique in presence of air using boron as flux and urea as a fuel. A comparative study of the prepared materials was carried out with and without the addition of boric acid. The boric acid was playing the important role of flux and reducer simultaneously. The peaks available in the XPS spectra of BaAl2O4:Eu2+ at 1126.5 and 1154.8 eV was ascribed to Eu2+(3d5/2) and Eu2+(3d3/2) respectively which confirmed the presence of Eu2+ ion in the prepared lattice. Morphology of phosphors was characterized by tunneling electron microscopy. XRD patterns revealed a dominant phase characteristics of hexagonal BaAl2O4 compound and the presence of dopants having unrecognizable effects on basic crystal structure of BaAl2O4. The addition of boric acid showed a remarkable change in luminescence properties and crystal size of nanophosphors. The emission spectra of phosphors had a broad band with maximum at 490–495 nm due to electron transition from 4f65d1 → 4f7 of Eu2+ ion. The codoping of the rare earth (RE3+=Y, Pr) ions help in the enhancement of their luminescent properties. The prepared phosphors had brilliant optoelectronic properties that can be properly used for solid state display device applications.The authors gratefully recognize the financial support from the University Grant Commission (UGC), New Delhi [MRP-40-73/2011(SR)] and the European Commission through Nano CIS project (FP7-PEOPLE-2010-IRSES ref. 269279).Singh, D.; Tanwar, V.; Simantilke, AP.; Marí, B.; Kadyan, PS.; Singh, I. (2016). Rapid synthesis and enhancement in down conversion emission properties of BaAl2O4:Eu2+,RE3+ (RE3+=Y, Pr) nanophosphors. Journal of Materials Science: Materials in Electronics. 27(3):2260-2266. https://doi.org/10.1007/s10854-015-4020-1S22602266273J.S. Kim, P.E. Jeon, J.C. Choi, H.L. Park, S.I. Mho, G.C. Kim, Appl Phys Lett 84, 2931 (2004)D. Jia, D.N. Hunter, J Appl Phys 100, 1131251 (2006)H. Aizawa, T. Katsumata, J. Takahashi, K. Matsunaga, S. Komuro, T. Morikawa, E. Toba, Rev Sci Instrum 74, 1344 (2003)C.N. Xu, X.G. Zheng, M. Akiyama, K. Nonaka, T. Watanabe, Appl Phys Lett 76, 179 (2000)C. Feldmann, T. Justel, C.R. Ronda, P.J. Schmidt, Adv Funct Mater 13, 511 (2004)P.J. Saines, M.M. Elcombe, B.J. Kennedy, J Solid State Chem 179, 613 (2006)R. Sakai, T. Katsumata, S. Komuro, T. Morikawa, J Lumin 85, 149 (1999)T. Aitasalo, P. Deren, J Solid State Chem 171, 114 (2003)S. Nakamura, T. Mukai, M. Senoh, J Appl Phys 76, 8189 (1994)S.H.M. Poort, G. Blasse, J Lumin 72, 247 (1997)P. Mingying, H. Guangyan, J Lumin 127, 735 (2007)X. Linjiu, H. Mingrui, T. Yanwen, C. Yongjie, K. Tomoaki, Z. Liqing, W. Ning, Jap J Applied Physics 46, 5871 (2007)T. Aitasalo, J. Hölsä, H. Jungner, M. Lastusaari, J. Niittykoski, J Phys Chem B 110, 4589 (2006)R. Stefani, L.C.V. Rodrigues, C.A.A. Carvalho, M.C.F.C. Felinto, H.F. Brito, M. Lastusaari, J. Hölsä, Opt Mater 31, 1815 (2009)M. Peng, G. Hong, J Lumin 127, 735 (2007)V. Singh, V. Natarajan, J.J. Zhu, Opt Mater 29, 1447 (2007)X.Y. Chen, C. Ma, X.X. Li, C.W. Shi, X.L. Li, D.R. Lu, J Phys Chem C 113, 2685 (2009)A.J. Zarur, J.Y. Ying, Nature 403, 65 (2000)J. Chen, F. Gu, C. Li, Cry Growth Des 8, 3175 (2008)J. Zhang, M. Yang, H. Jin, X. Wang, X. Zhao, X. Liu, L. Peng, Mater Res Bull 47, 247 (2012)P. Maślankiewicz, J. Szade, A. Winiarski, Ph Daniel, Cryst Res Technol 40, 410 (2005)Y.J. Chen, G.M. Qiu, Y.B. Sun et al., J Rare Earths 20, 50 (2002)F.C. Palilla, A.K. Levine, M.R. Tomkus, J Electrochem Soc 115, 642 (1968)J. Niittykoski, T. Aitasalo, J. Holsa, H. Jungner, M. Lastusaari, M. Parkkinen, M. Tukia, J Alloys Compd 374, 108 (2004)A. Nag, T.R.N. Kutty, J Alloys Compd 354, 221 (2003)D. Haranath, P. Sharma, H. Chander, J Phys D Appl Phys 38, 371 (2005

Orexin Neurons Receive Glycinergic Innervations

Glycine, a nonessential amino-acid that acts as an inhibitory neurotransmitter in the central nervous system, is currently used as a dietary supplement to improve the quality of sleep, but its mechanism of action is poorly understood. We confirmed the effects of glycine on sleep/wakefulness behavior in mice when administered peripherally. Glycine administration increased non-rapid eye movement (NREM) sleep time and decreased the amount and mean episode duration of wakefulness when administered in the dark period. Since peripheral administration of glycine induced fragmentation of sleep/wakefulness states, which is a characteristic of orexin deficiency, we examined the effects of glycine on orexin neurons. The number of Fos-positive orexin neurons markedly decreased after intraperitoneal administration of glycine to mice. To examine whether glycine acts directly on orexin neurons, we examined the effects of glycine on orexin neurons by patch-clamp electrophysiology. Glycine directly induced hyperpolarization and cessation of firing of orexin neurons. These responses were inhibited by a specific glycine receptor antagonist, strychnine. Triple-labeling immunofluorescent analysis showed close apposition of glycine transporter 2 (GlyT2)-immunoreactive glycinergic fibers onto orexin-immunoreactive neurons. Immunoelectron microscopic analysis revealed that GlyT2-immunoreactive terminals made symmetrical synaptic contacts with somata and dendrites of orexin neurons. Double-labeling immunoelectron microscopy demonstrated that glycine receptor alpha subunits were localized in the postsynaptic membrane of symmetrical inhibitory synapses on orexin neurons. Considering the importance of glycinergic regulation during REM sleep, our observations suggest that glycine injection might affect the activity of orexin neurons, and that glycinergic inhibition of orexin neurons might play a role in physiological sleep regulation

Use of humanised rat basophilic leukaemia cell line RS-ATL8 for the assessment of allergenicity of Schistosoma mansoni proteins.

BACKGROUND Parasite-specific IgE is thought to correlate with protection against Schistosoma mansoni infection or re-infection. Only a few molecular targets of the IgE response in S. mansoni infection have been characterised. A better insight into the basic mechanisms of anti-parasite immunity could be gained from a genome-wide characterisation of such S. mansoni allergens. This would have repercussions on our understanding of allergy and the development of safe and efficacious vaccinations against helminthic parasites. METHODOLOGY/PRINCIPAL FINDINGS A complete medium- to high-throughput amenable workflow, including important quality controls, is described, which enables the rapid translation of S. mansoni proteins using wheat germ lysate and subsequent assessment of potential allergenicity with a humanised Rat Basophilic Leukemia (RBL) reporter cell line. Cell-free translation is completed within 90 minutes, generating sufficient amounts of parasitic protein for rapid screening of allergenicity without any need for purification. Antigenic integrity is demonstrated using Western Blotting. After overnight incubation with infected individuals' serum, the RS-ATL8 reporter cell line is challenged with the complete wheat germ translation mixture and Luciferase activity measured, reporting cellular activation by the suspected allergen. The suitability of this system for characterization of novel S. mansoni allergens is demonstrated using well characterised plant and parasitic allergens such as Par j 2, SmTAL-1 and the IgE binding factor IPSE/alpha-1, expressed in wheat germ lysates and/or E. coli. SmTAL-1, but not SmTAL2 (used as a negative control), was able to activate the basophil reporter cell line. CONCLUSION/SIGNIFICANCE This method offers an accessible way for assessment of potential allergenicity of anti-helminthic vaccine candidates and is suitable for medium- to high-throughput studies using infected individual sera. It is also suitable for the study of the basis of allergenicity of helminthic proteins

Augmentation of Reverse Transcription by Integrase through an Interaction with Host Factor, SIP1/Gemin2 Is Critical for HIV-1 Infection

There has been accumulating evidence for the involvement of retroviral integrase (IN) in the reverse transcription of viral RNA. We previously identified a host factor, survival motor neuron-interacting protein 1 (SIP1/Gemin2) that binds to human immunodeficiency virus type 1 (HIV-1) IN and supports HIV-1 infection apparently at reverse transcription step. Here, we demonstrated that HIV-1 IN together with SIP1 augments reverse transcriptase (RT) activity by enhancing the assembly of RT on viral RNA in vitro. Synthetic peptides corresponding to the binding motifs within IN that inhibited the IN-SIP1 interaction abrogated reverse transcription in vitro and in vivo. Furthermore, knockdown of SIP1 reduced intracellular stability and multimer formation of IN through proteasome-mediated degradation machinery. Taken together, SIP1 appears to stabilize functional multimer forms of IN, thereby promoting the assembly of IN and RT on viral RNA to allow efficient reverse transcription, which is a prerequisite for efficient HIV-1 infection