Principal component analysis of three-dimensional face shape: Identifying shape features that change with age

Abstract

Background

The types of shape feature that constitutes a face have not been comprehensively established, and most previous studies of age-related changes in facial shape have focused on individual characteristics, such as wrinkle, sagging skin, etc. In this study, we quantitatively measured differences in face shape between individuals and investigated how shape features changed with age.

Methods

We analyzed three-dimensionally the faces of 280 Japanese women aged 20-69 years and used principal component analysis to establish the shape features that characterized individual differences. We also evaluated the relationships between each feature and age, clarifying the shape features characteristic of different age groups.

Results

Changes in facial shape in middle age were a decreased volume of the upper face and increased volume of the whole cheeks and around the chin. Changes in older people were an increased volume of the lower cheeks and around the chin, sagging skin, and jaw distortion.

Conclusion

Principal component analysis was effective for identifying facial shape features that represent individual and age-related differences. This method allowed straightforward measurements, such as the increase or decrease in cheeks caused by soft tissue changes or skeletal-based changes to the forehead or jaw, simply by acquiring three-dimensional facial images.

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Glial control of neurogenesis

Publication date: December 2017
Source:Current Opinion in Neurobiology, Volume 47
Author(s): Sven Falk, Magdalena Götz
Glial cells are central components of all neurogenic niches in the embryonic as well as in the adult central nervous system. While neural stem cells (NSCs) themselves exhibit glial features the behavior of NSCs is also strongly influenced by niche glial cells. Recently, studies have begun to uncover a large variety of glial cell-extrinsic as well as intrinsic factors that play crucial roles in the control of NSCs and the regulation of the cellular output from the neurogenic niches. In this review, we focus on mechanisms underlying the formation of adult NSCs by embryonic radial glia cells, discuss the influence of niche glia cells on adult NSCs and examine how the neurogenic potential of glial cells is controlled.



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Outcomes following completion and salvage surgery for early rectal cancer: a systematic review

Publication date: Available online 14 November 2017
Source:European Journal of Surgical Oncology
Author(s): Helen JS. Jones, Chris Cunningham, Gary A. Nicholson, Roel Hompes
ObjectivesTo establish outcomes after completion and salvage surgery following local excision in literature published since 2005, to inform decision-making when offering local excision.BackgroundLocal excision of early rectal cancer aims to offer cure while maintaining quality of life through organ preservation. However, some patients will require radical surgery, prompted by unexpected poor pathology or local recurrence. Consistent definition and reporting of these scenarios is poor. We propose the term "salvage surgery" for recurrence after local excision and "completion surgery" for poor pathology.MethodsElectronic databases were searched in February 2016. Studies since 2005 describing outcomes for radical surgery following local excision of rectal cancer were included. Pooled and average values were obtained.ResultsA total of 23 studies included 262 completion and 165 salvage operations. Most completion operations were done within 4 weeks; local recurrence rate was 5% and overall disease recurrence rate was 14%.The majority of salvage operations for local recurrence were within 15 months of local excision, often following adjuvant treatment. Re-do local excision was used in 15%; APR was the most common radical procedure. Further local recurrence was uncommon (3%) but overall disease recurrence rate was 13%. Estimated 5-year survival was in the order of 50%. Heterogeneity was high among the studies.ConclusionsPatients undergoing local excision must be informed of risks and expected outcomes, but better data on completion and salvage surgery are required to achieve this.



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Breast Lesion Excision System in the diagnosis and treatment of intraductal papillomas – a feasibility study

Publication date: Available online 14 November 2017
Source:European Journal of Surgical Oncology
Author(s): Laura Niinikoski, Katja Hukkinen, Marjut H.K. Leidenius, Anders Ståhls, Tuomo J. Meretoja
ObjectivesThis study aims to evaluate the feasibility of Breast Lesion Excision System (BLES) in the treatment of intraductal papillomas.Material and methodsAll patients with a needle biopsy –based suspicion of an intraductal papilloma who consequently underwent a BLES procedure at Helsinki University Hospital between 2011 and 2016 were included in this retrospective study. The purpose of the BLES procedure was either to excise the entire lesion or in few cases to achieve better sampling.ResultsIn total, 74 patients underwent 80 BLES procedures. Pathological diagnosis after the BLES biopsy confirmed an intraductal papilloma without atypia in 43 lesions, whereas 10 lesions were upgraded to high-risk lesions (HRL) with either atypical ductal hyperplasia or lobular carcinoma in situ. Five cases were upgraded to malignancy, two were invasive ductal carcinomas and three were ductal carcinoma in situ. Additionally, 18 lesions were diagnosed as other benign lesions. Four procedures failed. Complete excision with BLES was achieved in 19 out of 43 intraductal papillomas, 6 out of 10 HRL and two out of five malignant lesions. No major complications occurred. The BLES procedure was adequate in the management of the 71 breast lesions.ConclusionThe BLES procedure is an acceptable method for the management of small benign and high-risk breast lesions such as intraductal papillomas in selected patients. Thus, a great amount of diagnostic surgical biopsies can be avoided.



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High-throughput approaches for screening and analysis of cell behaviors

Publication date: January 2018
Source:Biomaterials, Volume 153
Author(s): Jungmok Seo, Jung-Youn Shin, Jeroen Leijten, Oju Jeon, Gulden Camci-Unal, Anna D. Dikina, Katelyn Brinegar, Amir M. Ghaemmaghami, Eben Alsberg, Ali Khademhosseini
The rapid development of new biomaterials and techniques to modify them challenge our capability to characterize them using conventional methods. In response, numerous high-throughput (HT) strategies are being developed to analyze biomaterials and their interactions with cells using combinatorial approaches. Moreover, these systematic analyses have the power to uncover effects of delivered soluble bioactive molecules on cell responses. In this review, we describe the recent developments in HT approaches that help identify cellular microenvironments affecting cell behaviors and highlight HT screening of biochemical libraries for gene delivery, drug discovery, and toxicological studies. We also discuss HT techniques for the analyses of cell secreted biomolecules and provide perspectives on the future utility of HT approaches in biomedical engineering.



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Bone mesenchymal stem cell secretion of sRANKL/OPG/M-CSF in response to macrophage-mediated inflammatory response influences osteogenesis on nanostructured Ti surfaces

Publication date: February 2018
Source:Biomaterials, Volume 154
Author(s): Qian-li Ma, Liang Fang, Nan Jiang, Liang Zhang, Ying Wang, Yu-mei Zhang, Li-hua Chen
Although it has been well established that osteogenic differentiation of bone mesenchymal stem cells (bMSCs) as well as osteoclastic differentiation of macrophages can be manipulated by the nanostructure of biomaterial surfaces, the interactions among the effects of the surface on immune cells and bMSCs remained unknown. Therefore, in this study, the osteogenic behaviors and secretion of osteoclastogenesis-related cytokines of human bMSCs on TiO2 nanotubular (NT) surfaces in conditioned medium (CM) generated by macrophages cultured on the respective NT surfaces (NT-CM) were analyzed. Although bMSCs showed consistent osteogenic behaviors on the NT5 and NT20 surfaces in both standard culture medium and both types of NT-CM, collagen synthesis and extracellular matrix mineralization were partially impeded on the NT20 surface in NT20-CM and bMSC cytokine secretions on the NT20 surface in NT20-CM elicited remarkable multinuclear giant cell and osteoclast formation compared with that observed on the NT5 surface in NT5-CM. After implantation in vivo, mineralized bone formation was significantly delayed around the NT20 implant compared with the NT5 implant, but both surfaces contributed to good bone formation after 12 weeks. The results obtained in this study advance our understanding of the confounding influence of the implant surface nanostructure, macrophage inflammatory response, and osteogenic differentiation of bMSCs as well as the retro-regulative effects of bMSCs on the osteoclastic differentiation of macrophages, and the culture system based on different NT surfaces and CM generated on the respective surfaces may provide a systematic research model for evaluating the performance of endosseous implants as well as a prospective approach for improving implant osseointegration via immune-regulation.



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Albumin-coordinated assembly of clearable platinum nanodots for photo-induced cancer theranostics

Publication date: February 2018
Source:Biomaterials, Volume 154
Author(s): Yong'an Tang, Tao Yang, Qiaoli Wang, Xiaoyan Lv, Xue Song, Hengte Ke, Zhengqing Guo, Xiaoqing Huang, Jun Hu, Zifu Li, Peng Yang, Xiangliang Yang, Huabing Chen
Photoactive noble metal nanoparticles are of increasing importance toward personalized cancer therapy in the field of precision nanomedicine. A critical challenge remains in the exploration of clinically potential noble metal nanoparticles for highly efficient cancer theranostics. Here, we introduce albumin-coordinated assembly of clearable Pt nanodots (Pt-NDs) with monodisperse nanostructure as high-performance theranostic agents for imaging-guided photothermal tumor ablation. We precisely manipulate the reduction and growth of tetravalent Pt ions into ultrasmall nanodots through albumin-directed growth kinetics, thereby leading to the synthesis of monodisperse 6.7 nm Pt-NDs with albumin molecules as the corona. Pt-NDs exhibit the surface plasmon resonance at 225 nm with enhanced near-infrared (NIR) absorbance, ideal resistance to photo-bleaching, distinct photoacoustic and X-ray signals, as well as remarkable photothermal effect through non-radiative relaxation under NIR light irradiation. In particular, Pt-NDs possess preferable tumor accumulation, and effective in vivo excretory capability. Thus, these nanodots promote preferable in vivo microscopic photoacoustics and spatially anatomic CT imaging with enhanced contrast, as well as potent hyperthermia-mediated tumor ablation. These findings represent a facile and general approach to fabricate high-performance noble metal nanostructures with clinical potential for cancer theranostics.

Graphical abstract

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Biological safety and tissue distribution of (16-mercaptohexadecyl)trimethylammonium bromide-modified cationic gold nanorods

Publication date: February 2018
Source:Biomaterials, Volume 154
Author(s): Monika Zarska, Michal Sramek, Filip Novotny, Filip Havel, Andrea Babelova, Blanka Mrazkova, Oldrich Benada, Milan Reinis, Ivan Stepanek, Kamil Musilek, Jiri Bartek, Monika Ursinyova, Ondrej Novak, Rastislav Dzijak, Kamil Kuca, Jan Proska, Zdenek Hodny
The exceptionally high cellular uptake of gold nanorods (GNRs) bearing cationic surfactants makes them a promising tool for biomedical applications. Given the known specific toxic and stress effects of some preparations of cationic nanoparticles, the purpose of this study was to evaluate, in an in vitro and in vivo in mouse, the potential harmful effects of GNRs coated with (16-mercaptohexadecyl)trimethylammonium bromide (^MTABGNRs). Interestingly, even after cellular accumulation of high amounts of ^MTABGNRs sufficient for induction of photothermal effect, no genotoxicity (even after longer-term accumulation), induction of autophagy, destabilization of lysosomes (dominant organelles of their cellular destination), alterations of actin cytoskeleton, or in cell migration could be detected in vitro. In vivo, after intravenous administration, the majority of GNRs accumulated in mouse spleen followed by lungs and liver. Microscopic examination of the blood and spleen showed that GNRs interacted with white blood cells (mononuclear and polymorphonuclear leukocytes) and thrombocytes, and were delivered to the spleen red pulp mainly as GNR-thrombocyte complexes. Importantly, no acute toxic effects of ^MTABGNRs administered as 10 or 50 μg of gold per mice, as well as no pathological changes after their high accumulation in the spleen were observed, indicating good tolerance of ^MTABGNRs by living systems.

Graphical abstract

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A robust strategy for preparation of sequential stimuli-responsive block copolymer prodrugs via thiolactone chemistry to overcome multiple anticancer drug delivery barriers

Publication date: February 2018
Source:Biomaterials, Volume 154
Author(s): Wendong Ke, Wei Yin, Zengshi Zha, Jean Felix Mukerabigwi, Weijian Chen, Yuheng Wang, Chuanxin He, Zhishen Ge
Block copolymer prodrugs (BCPs) have attracted considerable attentions in clinical translation of nanomedicine owing to their self-assembly into well-defined core-shell nanoparticles for improved pharmacokinetics, stability in blood circulation without drug leakage, and optimized biodistribution. However, a cascade of physiological barriers against specific delivery of drugs into tumor cells limit the final therapeutic efficacy. Herein, we report a robust and facile strategy based on thiolactone chemistry to fabricate well-defined BCPs with sequential tumor pH-promoted cellular internalization and intracellular stimuli-responsive drug release. A series of BCPs were prepared through one-pot synthesis from clinically used small molecule anticancer drugs. The ring-opening reaction of drug-conjugated thiolactones releases mercapto groups via aminolysis by N-(3-aminopropyl)-imidazole, which further react with poly(ethylene glycol)-block-poly(pyridyldisulfide ethylmethacrylate) (PEG-PDSEMA) to produce imidazole and disulfide bonds-incorporated BCPs. Taking paclitaxel (PTX) for example, PTX BCPs exhibited high drug-loading content (>50%) and low critical micellization concentration (5 × 10⁻³ g/L), which can self-assemble into micellar nanoparticles in aqueous solution with a small size (∼40 nm). The nanoparticles showed high tumor accumulation and uniform distribution in hypopermeable tumors via systemic administration. Meanwhile, imidazole moieties endow nanoparticles tumor pH-sensitive charge transition from nearly neutral to positive, which promoted cellular internalization. Disulfide bonds can be cleaved by intracellular glutathione (GSH) of cancer cells, which accelerate the release of active PTX drug inside cells. Finally, highly aggressive murine breast cancer 4T1 tumor and hypopermeable human pancreatic adenocarcinoma BxPC3 tumor were completely ablated after treatment by PTX BCP nanoparticles. Consequently, the robust and facile preparation strategy based on thiolactone chemistry represents an efficient approach to construct multifunctional BCPs for better therapeutic efficacy via addressing multiple physiological barriers.

Graphical abstract

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Editorial board

Publication date: January 2018
Source:Biomaterials, Volume 153





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Parenting and family adjustment scales (PAFAS): validation of a brief parent-report measure for use with families who have a child with a developmental disability

Publication date: January 2018
Source:Research in Developmental Disabilities, Volume 72
Author(s): Trevor G. Mazzucchelli, Julie Hodges, Robert T. Kane, Kate Sofronoff, Matthew R. Sanders, Stewart Einfeld, Bruce Tonge, Kylie M. Gray
BackgroundChildren with a developmental disability are three to four times more likely than their typically developing peers of developing significant emotional and behavioural problems. There is strong evidence to suggest that individual biological and psychological factors interact with family functioning to precipitate and perpetuate these problems.AimsThis study examined the psychometric properties of a brief measure, the Parent and Family Adjustment Scales (PAFAS) for use with parents of children with a developmental disability.MethodsA sample of 914 parents of children (M=6.27years) with a developmental disability participated in the study. Disabilities included Autism Spectrum Disorder and Intellectual DisabilityResultsA confirmatory factor analysis supported a 16-item, four factor model of PAFAS Parenting, and an 11-item, three factor model of PAFAS Family Adjustment. The Parenting Scale measures parental consistency, coercive practices, use of encouragement and the quality of parent-child relationship. The Family Adjustment Scale measures parental emotional adjustment and partner and family support in parenting.ConclusionsThe current study indicated that the PAFAS demonstrates promise as a brief measure of multiple domains of family functioning important for families who have a child with a developmental disability.



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Editorial Board

Publication date: January 2018
Source:Microbiological Research, Volume 206





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Functional characterization of murB-potABCD operon for polyamine uptake and peptidoglycan synthesis in Streptococcus suis

Publication date: Available online 14 November 2017
Source:Microbiological Research
Author(s): Wanquan Liu, Meifang Tan, Chunyan Zhang, Zhuofei Xu, Lu Li, Rui Zhou
Spermidine (Spd), spermine (Spm), and putrescine (Put), which are the most widely distributed cellular polyamines, are essential for normal growth and multiplication of both eukaryotic and prokaryotic cells. In this study, we identified the only putative polyamine transport system PotABCD in Streptococcus suis, a worldwide zoonotic Gram-positive pathogen causing lethal infections in humans and pigs. It was discovered that S. suis could uptake polyamines preferably Spd and Spm. By constructing a potA deleted mutant, we confirmed that PotABCD was responsible for polyamine uptake, and PotD bound to the protein of polyamines. The four PotABCD genes were co-transcribed with murB, a gene involved in peptidoglycan (PG) synthesis. Furthermore the roles of polyamine transport system in maintaining the PG structure were detected to understand the biological significance of this co-transcription. In contrast to the wild type, the mutant ΔpotA exhibited elongated chain length and abnormal cell division morphology. Phenotypic changes were attributed to be the up-regulation of genes involved in PG synthesis and hydrolysis in ΔpotA. Additionally, polyamines functioned not only as feedback regulators of PotA by inhibiting PotA activity but also as regulators on potABCD and genes involved in PG synthesis. This study reveals the functions of PotABCD in polyamine transport and the regulatory roles of polyamines in PG synthesis.Results provide new insights into the machineries contributing to normal growth and cell division of S. suis.



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DNA sequence-specific dimeric bisbenzimidazoles DBP(n) and DBPA(n) as inhibitors of H-NS silencing in bacterial cells

Publication date: Available online 14 November 2017
Source:Microbiological Research
Author(s): Olga E. Melkina, Vasilii S. Koval, Alexander A. Ivanov, Alexei L. Zhuze, Gennadii B. Zavilgelsky
DNA sequence-specific fluorescent dimeric bisbenzimidazoles DBP(n) and DBPA(n), noncovalently interacting with A-T pairs in the minor groove of double-stranded DNA were used for studying and monitoring the expression of histone-like H-NS-dependent promoters. Histone-like H-NS selectively binds to AT-rich segments of DNA and silences a large number of genes in bacterial chromosomes. The H-NS-dependent promoters of Quorum Sensing (QS)-regulated lux operons of the marine bacteria mesophilic Aliivibrio fischeri, psychrophilic Aliivibrio logei were used. Escherichia coli lux biosensors were constructed by cloning fragments bearing QS-regulated promoters into the vector, thereby placing each fragment upstream of the promoterless Photorhabdus luminescens luxCDABE genes. It was shown that the dimeric bisbenzimidazoles DBP(n) and DBPA(n) counteract the H-NS silencing activity. Thus, the presence of DBP(n) or DBPA(n) in the medium leads to an approximately 10-100-fold increase in the level of transcription of QS promoters in E. coli hns⁺. The largest decrease in the level of H-NS repression was observed using ligands containing a linker with a length of ca. 18Å, such as DBP(2) and DBPA(2). Ligands containing linkers with n=1 and 3 are an order of magnitude less active; ligands with n=4 are inactive. DBPA(2) exhibits activity starting with a concentration of 0.5μM; the minimum concentration of DBP(2) is 5–7 times higher. It is suggested that A-T pairs located at five nucleotide pair intervals, which correspond to the linker length in highly active ligands with n=2, play a key role in the structure of H-NS-binding sites in QS-regulated promoters.



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Ontogenetic stage, plant vigor and sex mediate herbivory loads in a dioecious understory herb

Publication date: Available online 14 November 2017
Source:Acta Oecologica
Author(s): Sara Selaković, Vukica Vujić, Nemanja Stanisavljević, Živko Jovanović, Svetlana Radović, Dragana Cvetković
Plant-herbivore interactions can be mediated by plant apparency, defensive and nutritional quality traits that change through plant ontogeny, resulting in age-specific herbivory. In dioecious species, opposing allocation patterns in defense may lead to sex-biased herbivory. Here, we examine how onto stage and plant sex determine levels of herbivore damage in understory herb Mercurialis perennis under field conditions. We analyzed variation in plant size (height, total leaf area), physical (specific leaf area) and chemical (total phenolic and condensed tannins contents) defense, and nutritional quality (total water, soluble protein and nonstructural carbohydrate contents) during the shift from reproductive to post-reproductive stage. Furthermore, we explored correlations between the analyzed traits and levels of foliar damage. Post-reproductive plants had lower levels of chemical defense, and larger leaf area removed, in spite of having lower nutritive quality. Opposing patterns of intersexual differences were detected in protein and phenolic contents during reproductive stage, while in post-reproductive stage total leaf area was sexually dimorphic. Female-biased herbivory was apparent only after reproduction. Plant size parameters combined with condensed tannins content determined levels of foliar damage during post-reproductive stage, while the only trait covarying with herbivory in reproductive stage was total nonstructural carbohydrate content. Our results support claims of optimal defense theory – sensitive stage of reproduction was better defended. We conclude that different combinations of plant traits mediated interactions with herbivores in mature stages. Differences in reproductive allocation between the sexes may not immediately translate into different levels of damage, stressing the need for considering different ontogenetic stages when exploring sex bias in herbivory.



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Discovery of novel purine nucleoside derivatives as phosphodiesterase 2 (PDE2) inhibitors: structure-based virtual screening, optimization and biological evaluation

Publication date: Available online 14 November 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Xiaoxia Qiu, Yiyou Huang, Deyan Wu, Fei Mao, Jin Zhu, Wenzhong Yan, Hai-Bin Luo, Jian Li
Phosphodiesterase 2 (PDE2) has received much attention for the potential treatment of the central nervous system (CNS) disorders and pulmonary hypertension. Herein, we identified that clofarabine (4), an FDA-approved drug, displayed potential PDE2 inhibitory activity (IC50 = 3.12 ± 0.67 μM) by structure-based virtual screening and bioassay. Considering the potential therapeutic benefit of PDE2, a series of purine nucleoside derivatives based on the structure and binding mode of 4 were designed, synthesized and evaluated, which led to the discovery of the best compound 14e with a significant improvement of inhibitory potency (IC50 = 0.32 ± 0.04 μM). Further molecular docking and molecular dynamic (MD) simulations studies revealed that 5'-benzyl group of 14e could interact with the unique hydrophobic pocket of PDE2 by forming extra van der Waals interactions with hydrophobic residues such as Leu770, Thr768, Thr805 and Leu809, which might contribute to its enhancement of PDE2 inhibition. These potential compounds reported in this article and the valuable structure-activity relationships (SARs) might bring significant instruction for further development of potent PDE2 inhibitors.

Graphical abstract

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Bioluminescence Probe for γ-Glutamyl Transpeptidase Detection in vivo

Publication date: Available online 14 November 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Yuxing Lin, Yuqi Gao, Zhao Ma, Tianyu Jiang, Xin Zhou, Zhenzhen Li, Xiaojun Qin, Yun Huang, Lupei Du, Minyong Li
To detect γ-Glutamyl Transpeptidase (GGT) activity in vitro and in vivo, a bioluminescence probe with high sensitivity and specificity was well designed and synthesized. This probe can be recognized by GGT and release strong bioluminescence with its further reaction with luciferase. The performance of this probe was demonstrated in vitro and in cells. Finally, we applied the probe for detection of GGT activity in xenograft model.

Graphical abstract

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Bone marrow adipocytes in haematological malignancies

Publication date: Available online 14 November 2017
Source:Acta Histochemica
Author(s): Ewa Frączak, Mateusz Olbromski, Aleksandra Piotrowska, Natalia Glatzel-Plucińska, Piotr Dzięgiel, Jarosław Dybko, Kazimierz Kuliczkowski, Tomasz Wróbel
Bone marrow adipocytes (BMAs) derived from mesenchymal stem cells (MSC) are an active and significant element of the bone marrow microenvironment. They are involved in metabolic functions, complex interactions with other stromal cells, and in the development and progression of tumours. Currently, there is little data regarding the role of BMAs in haematological malignancies. Due to this, we have attempted to characterise the BMAs in these malignancies in terms of quantity and morphology. Our study included 30 patients aged 22–76 with myelo- (n=17) and lymphoproliferative malignancies (n=13), both with and without bone marrow infiltration. Trepanobioptate was the evaluated material. The number and diameter of BMAs were measured, and the percentage of adipocytes (adipocyte fraction – AF), hematopoietic cells (hematopoietic fraction – HF) and trabecular bone (trabecular bone fraction – BF) was calculated. The obtained results were considered against the clinical parameters of age, sex, body weight, body surface area (BSA) and body mass index (BMI). We observed that as age increases, the number of BMA/mm², the diameter of adipocytes and AF increase while BF and HF decrease. However, this relationship was not statistically significant. A significant correlation of BMA parameters was also not found in relation to weight, BMI and BSA, and the number and diameter of BMAs were comparable in both sexes. The trepanobioptate of infiltrated bone marrow showed a decreased number of BMA/mm² compared to the trepanobioptate from bone marrow without infiltration (97.44±69.16 vs. 164.14±54.16; p=0.010) with a marked difference in men (69.75±65.26 vs. 180.33±60.40; p=0.007). These trepanobioptate also showed an increase in the number of BMA/mm² with age (r=0.472; p=0.041), and with an increase of BMI, an increase in diameter of BMAs (r=0.625; p=0.007) and AF (r=0.546; p=0.023). The number and size of BMAs, as well as AF, BF and HF in patients with myeloproliferative malignancies did not differ significantly compared to patients with lymphoproliferative malignancies.



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Age-related vulnerability of pattern separation in C57BL/6J mice

Publication date: February 2018
Source:Neurobiology of Aging, Volume 62
Author(s): Aurélia Cès, Thibaut Burg, Karine Herbeaux, Céline Héraud, Jean-Bastien Bott, Ayikoe Guy Mensah-Nyagan, Chantal Mathis
Aging is associated with impaired performance in behavioral pattern separation (PS) tasks based on similarities in object features and in object location. These deficits have been attributed to functional alterations in the dentate gyrus (DG)-CA3 region. Animal studies suggested a role of adult-born DG neurons in PS performance. The present study investigated the effect of aging in C57BL/6J mice performing PS tasks based on either object features or object location. At the age of 18 months or more, performance was severely impaired in both tasks. Spatial PS performance declined gradually over adult lifespan from 3 to 21 months. Subchronic treatment with the cognitive enhancer D-serine fully rescued spatial PS performance in 18-month-old mice and induced a modest increase in the number of 4-week-old adult-born cells in the DG. Performance of mice in these PS tasks shows an age dependence, which appears to translate well to that found in humans. This model should help in deciphering physiological changes underlying PS deficits and in identifying future therapeutic targets.



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Prostaglandin J2 promotes O-GlcNAcylation raising APP processing by α- and β-secretases: relevance to Alzheimer's disease

Publication date: February 2018
Source:Neurobiology of Aging, Volume 62
Author(s): Teneka Jean-Louis, Patricia Rockwell, Maria E. Figueiredo-Pereira
Regulation of the amyloid precursor protein (APP) processing by α- and β-secretases is of special interest to Alzheimer's disease (AD), as these proteases prevent or mediate amyloid beta formation, respectively. Neuroinflammation is also implicated in AD. Our data demonstrate that the endogenous mediator of inflammation prostaglandin J2 (PGJ2) promotes full-length APP (FL-APP) processing by α- and β-secretases. The decrease in FL-APP was independent of proteasomal, lysosomal, calpain, caspase, and γ-secretase activities. Moreover, PGJ2-treatment promoted cleavage of secreted APP, specifically sAPPα and sAPPβ, generated by α and β-secretase, respectively. Notably, PGJ2-treatment induced caspase-dependent cleavage of sAPPβ. Mechanistically, PGJ2-treatment selectively diminished mature (O- and N-glycosylated) but not immature (N-glycosylated only) FL-APP. PGJ2-treatment also increased the overall levels of protein O-GlcNAcylation, which occurs within the nucleocytoplasmic compartment. It is known that APP undergoes O-GlcNAcylation and that the latter protects proteins from proteasomal degradation. Our results suggest that by increasing protein O-GlcNAcylation levels, PGJ2 renders mature APP less prone to proteasomal degradation, thus shunting APP toward processing by α- and β-secretases.



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Brain structural differences between 73- and 92-year olds matched for childhood intelligence, social background, and intracranial volume

Publication date: February 2018
Source:Neurobiology of Aging, Volume 62
Author(s): Stuart J. Ritchie, David Alexander Dickie, Simon R. Cox, Maria del C. Valdés Hernández, Ruth Sibbett, Alison Pattie, Devasuda Anblagan, Paul Redmond, Natalie A. Royle, Janie Corley, Susana Muñoz Maniega, Adele M. Taylor, Sherif Karama, Tom Booth, Alan J. Gow, John M. Starr, Mark E. Bastin, Joanna M. Wardlaw, Ian J. Deary
Fully characterizing age differences in the brain is a key task for combating aging-related cognitive decline. Using propensity score matching on 2 independent, narrow-age cohorts, we used data on childhood cognitive ability, socioeconomic background, and intracranial volume to match participants at mean age of 92 years (n = 42) to very similar participants at mean age of 73 years (n = 126). Examining a variety of global and regional structural neuroimaging variables, there were large differences in gray and white matter volumes, cortical surface area, cortical thickness, and white matter hyperintensity volume and spatial extent. In a mediation analysis, the total volume of white matter hyperintensities and total cortical surface area jointly mediated 24.9% of the relation between age and general cognitive ability (tissue volumes and cortical thickness were not significant mediators in this analysis). These findings provide an unusual and valuable perspective on neurostructural aging, in which brains from the 8th and 10th decades of life differ widely despite the same cognitive, socioeconomic, and brain-volumetric starting points.



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An interleaved sequence for simultaneous magnetic resonance angiography (MRA), susceptibility weighted imaging (SWI) and quantitative susceptibility mapping (QSM)

Publication date: Available online 14 November 2017
Source:Magnetic Resonance Imaging
Author(s): Yongsheng Chen, Saifeng Liu, Sagar Buch, Jiani Hu, Yan Kang, E. Mark Haacke
PurposeTo image the entire vasculature of the brain with complete suppression of signal from background tissue using a single 3D excitation interleaved rephased/dephased multi-echo gradient echo sequence. This ensures no loss of signal from fast flow and provides co-registered susceptibility weighted images (SWI) and quantitative susceptibility maps (QSM) from the same scan.Materials and methodsThe suppression of background tissue was accomplished by subtracting the flow-dephased images from the flow-rephased images with the same echo time of 12.5ms to generate a magnetic resonance angiogram and venogram (MRAV). Further, a 2.5ms flow-compensated echo was added in the rephased portion to provide sufficient signal for major arteries with fast flow. The QSM data from the rephased 12.5ms echo was used to suppress veins on the MRAV to generate an artery only MRA. The proposed approach was tested on five healthy volunteers at 3T.ResultsThis three-echo interleaved GRE sequence provided complete background suppression of stationary tissues, while the short echo data gave high signal in the internal carotid and middle cerebral arteries (MCA). The contrast-to-noise ratio (CNR) of the arteries was significantly improved in the M3 territory of the MCA compared to the non-linear subtraction MRA and TOF-MRA. Veins were suppressed successfully utilizing the QSM data.ConclusionThe background tissue can be properly suppressed using the proposed interleaved MRAV sequence. One can obtain whole brain MRAV, MRA, SWI, true-SWI (or tSWI) and QSM data simultaneously from a single scan.



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High frequency neurons determine effective connectivity in neuronal networks

Publication date: 1 February 2018
Source:NeuroImage, Volume 166
Author(s): Aref Pariz, Zahra G. Esfahani, Shervin S. Parsi, Alireza Valizadeh, Santiago Canals, Claudio R. Mirasso
The emergence of flexible information channels in brain networks is a fundamental question in neuroscience. Understanding the mechanisms of dynamic routing of information would have far-reaching implications in a number of disciplines ranging from biology and medicine to information technologies and engineering. In this work, we show that the presence of a node firing at a higher frequency in a network with local connections, leads to reliable transmission of signals and establishes a preferential direction of information flow. Thus, by raising the firing rate a low degree node can behave as a functional hub, spreading its activity patterns polysynaptically in the network. Therefore, in an otherwise homogeneous and undirected network, firing rate is a tunable parameter that introduces directionality and enhances the reliability of signal transmission. The intrinsic firing rate across neuronal populations may thus determine preferred routes for signal transmission that can be easily controlled by changing the firing rate in specific nodes. We show that the results are generic and the same mechanism works in the networks with more complex topology.



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Overlapping frontoparietal networks for tactile and visual parametric working memory representations

Publication date: 1 February 2018
Source:NeuroImage, Volume 166
Author(s): Yuan-hao Wu, Işıl Uluç, Timo Torsten Schmidt, Kathrin Tertel, Evgeniya Kirilina, Felix Blankenburg
Previous working memory (WM) research based on non-human primate electrophysiology and human EEG has shown that frontal brain regions maintain frequencies of flutter stimulation across different sensory modalities by means of a supramodal parametric WM code. These findings imply that frontal regions encode the memorized frequencies in a sensory-unspecific, quantitative format. Here, we explored which brain regions maintain information about frequencies provided by different sensory modalities at the level of activity pattern across fMRI voxel populations. Moreover, we sought evidence for a supramodal multivariate WM representation. Participants maintained the same set of frequencies of tactile vibration and visual flicker for a 6 s WM delay in a frequency discrimination task. A support vector regression model for multivariate pattern analysis was applied. We observed that sensory cortices were only selective for memoranda of their corresponding modalities, while frontoparietal regions exhibited distinguishable activity patterns to memorized frequencies regardless of sensory modality. A common multivariate code was not evident in our data. Collectively, we show that mnemonic representations for stimulus frequencies are maintained throughout the cortical hierarchy, in line with the suggested transformation of information across different representational formats. Although evidence for a supramodal multivariate code is absent, our findings underpin the generalized role of the frontoparietal cortex for maintaining quantitative information across sensory modalities.



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A direct comparison between ERP and fMRI measurements of food-related inhibitory control: Implications for BMI status and dietary intake

Publication date: 1 February 2018
Source:NeuroImage, Volume 166
Author(s): Kaylie A. Carbine, Kara M. Duraccio, C. Brock Kirwan, Nathan M. Muncy, James D. LeCheminant, Michael J. Larson
Obesity and maintaining a healthy diet have important implications for physical and mental health. One factor that may influence diet and obesity is inhibitory control. We tested how N2 and P3 amplitude, event-related potential (ERP) components that reflect inhibitory control, and functional magnetic resonance imaging (fMRI) activity in brain regions associated with inhibitory control differed toward high- and low-calorie food stimuli across BMI status. We also assessed the relationship between neural indices of food-related inhibitory control and laboratory and daily food intake. Fifty-four individuals (17 normal-weight; 18 overweight; 19 individuals with obesity) completed two food-based go/no-go tasks (one with high- and one with low-calorie foods as no-go stimuli), once during ERP data acquisition and once during fMRI data acquisition. After testing, participants were presented with an ad libitum weighed food buffet. Participants also recorded their food intake using the Automated Self-Administered 24-hour Dietary Recall (ASA24) system across four days. Individuals recruited more inhibitory control when withholding responses towards high-compared to low-calorie foods, although this effect was more consistent for N2 than P3 or fMRI assessments. BMI status did not influence food-related inhibitory control. A larger inhibitory response as measured by N2 amplitude was related to increased ASA24 food intake; P3 amplitude and fMRI region of interest activity did not predict ASA24 intake; neither method predicted food intake from the buffet. ERP and fMRI measurements show similar neural responses to food, although N2 amplitude may be somewhat more sensitive in detecting differences between food types and predicting self-reports of food intake.



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Putting Bandits Into Context: How Function Learning Supports Decision Making.

Author: Schulz, Eric; Konstantinidis, Emmanouil; Speekenbrink, Maarten

DOI: 10.1037/xlm0000463

Publication Date: POST AUTHOR CORRECTIONS, 13 November 2017

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Charge transport in graphene oxide

Publication date: Available online 14 November 2017
Source:Nano Today
Author(s): Dong Wook Chang, Jong-Beom Baek
The transport of ionic species in nano-fluidic channels has recently attracted tremendous interest in various research areas. This is because extraordinary nanoscale transport phenomena have been achieved in these materials, including ultrafast and highly selective ion movement. A variety of organic and inorganic materials have been employed to construct nano-channels or nano-pores with controlled sizes and dimensions. In particular, because of its unique two-dimensional planar architecture, as well as the possession of numerous oxygenated functionalities, GO has emerged as a promising building block for high-performance nano-fluidic ion channels. The simple exfoliation-reconstruction approach can readily assemble individual GO sheets into a free-standing, layered, film-like structure. In addition to its utilization as a versatile solid support for nano-fluidic ion transport, GO can play different but positive roles as a filler in composite electrolytes, as a mixed proton/electron conductor, and as a selective ion permeation membrane. Herein, we summarize the recent advances in the transport of ionic species within GO-based electrolytes. Moreover, the perspectives and current challenges of this promising field are discussed.

Graphical abstract

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Editorial Board

Publication date: 15 January 2018
Source:Materials & Design, Volume 138





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Inhibition of leukotriene B4 synthesis protects against early brain injury possibly via reducing the neutrophil-generated inflammatory response and oxidative stress after subarachnoid hemorrhage in rats

Publication date: 26 February 2018
Source:Behavioural Brain Research, Volume 339
Author(s): Zhen-Nan Ye, Ling-Yun Wu, Jing-Peng Liu, Qiang Chen, Xiang-Sheng Zhang, Yue Lu, Meng-Liang Zhou, Wei Li, Zi-Huan Zhang, Da-Yong Xia, Zong Zhuang, Chun-Hua Hang
Leukotriene B4 (LTB4) is a highly potent neutrophil chemoattractant and neutrophils induces inflammatory response and oxidative stress when they recruit to and infiltrate in the injuried/inflamed site, such as the brain parenchyma after aneurysmal subarachnoid hemorrhage (SAH). This study is to investigate the potential effects of inhibition of LTB4 synthesis on neutrophil recruitment, inflammatory response and oxidative stress, as well as early brain injury (EBI) in rats after SAH. A pre-chiasmatic cistern SAH model of rats was used in this experiment. SC 57461A was used to inhibit LTB4 synthesis via intracerebroventricular injection. The brain tissues of temporal lobe after SAH were analyzed. Neuronal injury, brain edema and neurological function were evaluated to investigate the development of EBI. We found that inhibition of LTB4 synthesis after SAH could reduce the level of myeloperoxidase, alleviate the inflammatory response and oxidative stress, and reduce neuronal death in the brain parenchyma, and ameliorate brain edema and neurological behavior impairment at 24h after SAH. These results suggest that inhibition of LTB4 synthesis might alleviate EBI after SAH possibly via reducing the neutrophil-generated inflammatory response and oxidative stress.



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Computed Tomography of Internal Hernias Following Laparoscopic Roux-en-Y Gastric Bypass Surgery

Publication date: Available online 14 November 2017
Source:Seminars in Ultrasound, CT and MRI
Author(s): Yoan Kagoma, Gabriela Gayer
Internal hernia in the postoperative laparoscopic Roux-en-Y patient is a diagnosis associated with significant morbidity and risk of death. The radiologist plays an instrumental role in workup of this patient group; however, the imaging assessment of these patients is not straightforward given their complex postsurgical anatomy. Multiple radiologic signs of internal hernia have been studied in the literature. This review article presents these signs with representative cases as well as a summary of their diagnostic accuracy.



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The Reconstruction of the Donor Site of DP Flap Using Thoracodorsal Artery Perforator Flap

Summary: We performed a new procedure for reconstruction of donor site of a deltopectoral (DP) flap. A 58-year-old man presented with a wide subcutaneous abscess, which was caused by acute mandibular osteomyelitis due to dental caries. On admission, the patient received a neck incision for drainage. However, necrosis of the neck skin was observed after drainage. The patient had an 8 × 10 cm skin and soft-tissue defect, which we covered with a DP flap (15 × 7 cm). The DP flap donor site was reconstructed using a 16 × 8 cm pedicled thoracodorsal artery perforator (TDAP) flap. There was no flap necrosis, abscess formation, or scar contracture of the DP region. Debulking of the TDAP flap was not required. The pedicled TDAP flap is useful for the reconstruction of the donor site of DP flap. In this report, we describe our operative procedure.

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Long-Term Patency of Twisted Vascular Pedicles in Perforator-Based Propeller Flaps

Background: Propeller flaps require torsion of the vascular pedicle of up to 180 degrees. Contrary to free flaps, where the relevance of an intact vascular pedicle has been documented, little is known regarding twisted pedicles of propeller flaps. As secondary surgeries requiring undermining of the flap are common in the extremities, knowledge regarding the necessity to protect the pedicle is relevant. The aim of this study was a long-term evaluation of the patency of vascular pedicle of propeller flaps. Methods: In a retrospective clinical study, 22 patients who underwent soft-tissue reconstruction with a propeller flap were evaluated after 43 months. A Doppler probe was used to locate and evaluate the patency of the vascular pedicle of the flap. Results: The flaps were used in the lower extremity in 19 cases, on the trunk in 3 cases. All flaps had healed. In all patients, an intact vascular pedicle could be found. Flap size, source vessel, or infection could therefore not be linked to an increased risk of pedicle loss. Conclusions: The vascular pedicle of propeller flaps remains patent in the long term. This allows reelevation and undermining of the flap. We therefore recommend protecting the pedicle in all secondary cases to prevent later flap loss.

http://ift.tt/2hzytbN

Quercetin attenuates collagen-induced arthritis by restoration of Th17/Treg balance and activation of Heme Oxygenase 1-mediated anti-inflammatory effect

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Yan Yang, Xu Zhang, Min Xu, Xin Wu, Feipeng Zhao, Chengzhi Zhao
Quercetin (QU) has been shown obvious anti-arthritic property in pre-clinical studies or clinical studies. Howbeit, the underlying mechanism of it is still not revealed distinctly and should be gotten further insight into. QU at a dosage of 150 mg/kg was administered orally in collagen-induced arthritis rats and then the clinical symptoms were monitored. The protein levels of Th17/Treg-related cytokines were determined by ELISA, and the mRNA levels of cytokines and transcription factors associated with the Th17 and Treg phenotypes were evaluated by real-time PCR, the proportions of Th17 and Treg cells were assessed by flow cytometry. The results showed that QU administration yielded an obvious mitigation of arthritic manifestations including high arthritic scores and paw edema, which was accompanied with decrement of Th17-related cytokines (IL-17A and IL-21) and increment of Treg-related cytokines (IL-10 and TGF-β). QU decreased the percentage of Th17 cells, while increased the percentage of Treg cells. In addition, the activation of NLRP3 inflammasome which plays a crucial role in the development of RA was determined and found that the protein expressions of NLRP3, Caspase-1 and IL-1β were diminished by QU significantly. Moreover, the protein levels of inflammatory mediators which were recognized as chief culprits in inflammatory reaction were assayed. The contents of inflammatory mediators inclusive of TNF-α, IL-1β, IL-6, PGE2, COX-2 and iNOS were down-regulated markedly by QU. But the inhibitory effect of QU on inflammatory mediators was nearly abolished by Heme Oxygenase 1 (HO-1) siRNA. Taken together, QU attenuates CIA via modulating the Th17/Treg balance, inhibiting NLRP3 inflammasome activation as well as activating HO-1-mediated anti-inflammatory response.

Graphical abstract

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Gold nanoparticles as an adjuvant: Influence of size, shape, and technique of combination with CpG on antibody production

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Lev A. Dykman, Sergey A. Staroverov, Alexander S. Fomin, Vitaly A. Khanadeev, Boris N. Khlebtsov, Vladimir A. Bogatyrev
Gold nanoparticles (GNPs) are advantageous as an adjuvant in the design of effective vaccines and in the preparation of high-affinity antibodies to haptens and complete antigens. Another method of activating immunocompetent cells with colloidal gold is to conjugate GNPs with CpG oligodeoxynucleotides (ODNs). We examined how the size and shape of GNPs and various combinations of GNPs and CpG ODNs 1826 affect the immune response. When animals were injected with a model antigen (BSA) coupled to gold nanospheres (diameters, 15 and 50nm), nanorods, nanoshells, and nanostars, the titers of the resultant antibodies differed substantially. The antibody titers decreased in the sequence GNPs-50nm>GNPs-15nm>nanoshells>nanostars>nanorods>native BSA. We conclude that 50 and 15nm gold nanospheres are the optimal antigen carrier and adjuvant for immunization. The highest titer of anti-BSA antibodies was detected in the blood serum of mice immunized simultaneously with BSA–GNP and CpG–GNP conjugates.

Graphical abstract

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Toll-like receptor 4 deficiency increases resistance in sepsis-induced immune dysfunction

Publication date: January 2018
Source:International Immunopharmacology, Volume 54
Author(s): Chao Cao, Yanfen Chai, Songtao Shou, Jun Wang, Ying Huang, Tao Ma
Sepsis constitutes a serious life-threatening syndrome associated with complications of deregulated inflammatory response against endotoxin/lipopolysaccharide (LPS)-mediated severe infection. Toll-like receptor 4 (TLR4) plays a critical role in the activation of innate immunity through recognition of LPS. However, the impact of TLR4 signaling on the development of sepsis-induced immune dysfunction remains unclear. The aim of this study was to investigate the effect of TLR4 on regulatory T cells (Tregs) and its potential mechanism. To simulate sepsis, male C57BL/6 (wild-type) and C57BL/10ScNJNJU (TLR4^−/−) mice were subjected to cecal ligation and puncture (CLP). After 24h, pro- and anti-inflammatory cytokine secretion, neutrophil and macrophage lung and liver infiltration were assessed to evaluate the sepsis-induced inflammatory response. The quantity and apoptotic rate of Tregs were measured. The expression of cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and forkhead/winged helix transcription factor p3 (Foxp3) were analyzed. Cytokine (i.e., TNF-α, IL-2, IL-10, and IL-4) secretion by Tregs in the cell suspensions and the suppressive activity on CD4⁺CD25⁻ T cell proliferation were also determined in vitro. At 24h after the CLP procedure, the wild-type mice exhibited increased Treg levels and expression, and secreted inflammatory factors in the serum were markedly overproduced. However, the TLR4^−/− mice attenuated the increased Treg expression and inflammatory factor overproduction. These results indicate that in a model of post-septic mice, TLR4 deficiency improves immune paralysis by attenuating Treg activity and restoring a pro-inflammatory cytokine balance. Thus, modulation of the TLR4 activity may be useful in preventing immune dysfunction in sepsis.



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Scholar : These new articles for Levant are available online

The online platform for Taylor & Francis Online content New for Levant and online now on Taylor & Francis Online: Book Reviews Ancient Cookware from the Levant: An Ethnoarchaeological Perspective Lisa Graham Pages: 1-2 | DOI: 10.1080/00758914.2017.1400739 Original Articles The birth, life and death of an Iron Age house at Tel 'Eton, Israel Avraham Faust , Hayah Katz , Yair Sapir, Assaf Avraham , Ofer Marder, Guy Bar-Oz, Ehud Weiss, Chen Auman-Chazan, Anat Hartmann-Shenkman, Tehila Sadiel, Oren Vilnay, Michael Tsesarsky , Pariente Sarah, Oren Ackermann, Natasha Timmer, Ofir Katz, Dafna Langgut & Mordechay Benzaquen Pages: 1-38 | DOI: 10.1080/00758914.2017.1388027 Review Recent Trends in the Study of Late Bronze Age Ceramics in Syro-Mesopotamia and Neighbouring Regions Mara T. Horowitz Pages: 1-3 | DOI: 10.1080/00758914.2017.1400736 Do you have original research that relates to present-day Japan and its recent historical development? Contemporary Japan welcomes your submissions. To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Hypofractionated radiotherapy for prostate cancer in the postoperative setting: what is the evidence so far?

Publication date: Available online 14 November 2017
Source:Cancer Treatment Reviews
Author(s): Cristina Picardi, Ioan Perret, Raymond Miralbell, Thomas Zilli
Postoperative external beam radiation therapy (EBRT) is a validated treatment option in the adjuvant setting for prostate cancer patients with aggressive pathological features following radical prostatectomy (RP) or as salvage modality in patients with biochemical recurrence after RP. Contemporary randomized phase III trials have provided evidence for using hypofractionation in the definitive treatment setting as an alternative to standard fractionated regimens.Biomathematical modeling for prostate cancer fractionated EBRT associated with widely available refined treatment delivery techniques such as volumetric modulated-arc therapy with image-guided RT may improve the therapeutic ratio. Nevertheless, the role of hypofractionation in the postoperative setting still remains investigational.In this systematic review of the literature we reviewed the role of hypofractionation for postoperative EBRT in the adjuvant or salvage setting in prostate cancer patients previously treated by RP. A favorable acute toxicity profile with, at least, as good biochemical control rates with hypofractionation has been suggested. And yet conflicting results have been reported concerning long-term genitourinary late toxicity. Prospective studies are eagerly awaited to assess the role of hypofractionation in the postoperative setting.



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Balancing the Benefits and Harms of Thyroid Cancer Surveillance in Survivors of Childhood, Adolescent and Young Adult cancer: Recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group in Collaboration with the PanCareSurFup Consortium

Publication date: Available online 14 November 2017
Source:Cancer Treatment Reviews
Author(s): SC. Clement, LCM. Kremer, FA. Verburg, JH. Simmons, M. Goldfarb, RP. Peeters, EK. Alexander, E. Bardi, E. Brignardello, LS. Constine, CA. Dinauer, VM. Drozd, F. Felicetti, E. Frey, A. Heinzel, MM. van den Heuvel-Eibrink, SA. Huang, TP. Links, K. Lorenz, RL. Mulder, SJ. Neggers, EJM. Nieveen van Dijkum, KC. Oeffinger, RR. van Rijn, SA. Rivkees, CM. Ronckers, AB. Schneider, R. Skinner, JD. Wasserman, T. Wynn, MM. Hudson, PC. Nathan, HM. Van Santen
Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality.



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Sexual function and sex hormones in breast cancer patients

Abstract

Purpose

Breast cancer patients (BCP) are at risk of female sexual dysfunction (FSD). Our aim was to clarify the effects of treatment strategies, and steroid hormones levels on FSD.

Methods

We enrolled 136 BCP (46.9 ± 0.8 years), and 122 completed questionnaires. BCP were divided into four groups: 22 women with advanced breast cancer on neoadjuvant therapy (NAT), 48 on adjuvant therapy (AT), 30 taking hormonal therapy (HT) and 22 with metastatic cancer on first line chemotherapy (FLT). Fifty-eight healthy women (43 ± 2.8 years) were enrolled as controls. FSD was evaluated by FSFI, and sexual distress was assessed with FSDS-R. We have collected demographic data, laboratory values, and LH, FSH, total testosterone (T), and estradiol (E2) levels.

Results

BCP showed a prevalence of FSD of 69%, total FSFI score was 17. FSDS-R was 8.3. FSD had a prevalence of 72 % in NAT, 65% in AT, 77% in metastatic BCP under FLT, 67% in HT, compared with a prevalence of 20% in controls. BCP showed lower E2 than normal values, as well as T. LH and FSH were significantly elevated than normal values. Total FSFI score was positively correlated with T in 122 BCP, no significant correlation was found between E2 and FSFI. Significant differences were found between NAT and HT in lubrication, pain domains and total FSDS-R score, AT and HT in pain domain, AT and NAT in lubrication domain.

Conclusions

BCP are at high risk of developing FSD both for treatment choice and hormonal status, but they have not sexually related personal distress.

http://ift.tt/2zC2deR

Sexual function and sex hormones in breast cancer patients

Abstract

Purpose

Breast cancer patients (BCP) are at risk of female sexual dysfunction (FSD). Our aim was to clarify the effects of treatment strategies, and steroid hormones levels on FSD.

Methods

We enrolled 136 BCP (46.9 ± 0.8 years), and 122 completed questionnaires. BCP were divided into four groups: 22 women with advanced breast cancer on neoadjuvant therapy (NAT), 48 on adjuvant therapy (AT), 30 taking hormonal therapy (HT) and 22 with metastatic cancer on first line chemotherapy (FLT). Fifty-eight healthy women (43 ± 2.8 years) were enrolled as controls. FSD was evaluated by FSFI, and sexual distress was assessed with FSDS-R. We have collected demographic data, laboratory values, and LH, FSH, total testosterone (T), and estradiol (E2) levels.

Results

BCP showed a prevalence of FSD of 69%, total FSFI score was 17. FSDS-R was 8.3. FSD had a prevalence of 72 % in NAT, 65% in AT, 77% in metastatic BCP under FLT, 67% in HT, compared with a prevalence of 20% in controls. BCP showed lower E2 than normal values, as well as T. LH and FSH were significantly elevated than normal values. Total FSFI score was positively correlated with T in 122 BCP, no significant correlation was found between E2 and FSFI. Significant differences were found between NAT and HT in lubrication, pain domains and total FSDS-R score, AT and HT in pain domain, AT and NAT in lubrication domain.

Conclusions

BCP are at high risk of developing FSD both for treatment choice and hormonal status, but they have not sexually related personal distress.

http://ift.tt/2zC2deR

A New Two Component Compression System Turning an Elastic Bandage into an Inelastic Compression Device: Interface Pressure, Stiffness, and Haemodynamic Effectiveness

Publication date: Available online 13 November 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Giovanni Mosti, Hugo Partsch
IntroductionBandage application does not exert consistent compression pressure, leading to extremely variable compression when applied to patients. A new elastic bandage can exert a predefined pressure independently of healthcare providers and the size of the wrapped limb. The bandage system includes a series of non-stretchable patches that when applied to the bandage make it stiff. The aim of this work was to assess, in an experimental setting, the venous ejection fraction (EF) from the lower leg and the tolerability of this new bandage in a group of patients affected by superficial venous incompetence.MethodsEF was measured using strain gauge plethysmography under baseline conditions and the bandage was applied with a supine pressure of 20 and 30 mmHg, with and without the stiff patches, in 25 patients with severe venous reflux in the great saphenous vein. The interface pressure of the bandages was measured simultaneously in the medial gaiter area.ResultsAll patients showed EF values that were significantly reduced compared with normal individuals. Elastic bandages with an average pressure of 20 and 30 mmHg in the supine position achieved a slight improvement in EF, and, after applying non-stretchable patches on the same bandage with similar resting pressure, EF was restored to its normal range (p < .001). Improvement in EF correlates with the pressure differences between standing and lying pressure and between muscle systole and diastole during exercise.ConclusionThis study confirms that inelastic is much more effective than elastic compression for improving impaired venous haemodynamics. The test material can be applied with a predetermined pressure, which considerably enhances the consistency of application, and it is easily transformed into an inelastic system just by applying stiff patches without any stretch and without significantly increasing the comfortable supine pressure.



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Hierarchical Bayesian models for the autonomic-based Concealed Information Test

Publication date: Available online 14 November 2017
Source:Biological Psychology
Author(s): Yusuke Shibuya, Kensuke Okada, Tokihiro Ogawa, Izumi Matsuda, Michiko Tsuneoka
The concealed information test (CIT) is a psychophysiological memory detection technique for examining whether an examinee recognizes crime-relevant information. In current statistical analysis practice, the autonomic responses are usually transformed into Z scores within individuals to remove inter- and intra-individual variability. However, this conventional procedure leads to overestimation of the effect size, specifically the standardized mean difference of the autonomic responses between the crime-relevant information and the crime-irrelevant information. In this study, we attempted to resolve this problem by modeling inter- and intra-individual variability directly using hierarchical Bayesian modeling. Five models were constructed and applied to CIT data obtained from 167 participants. The validity of the CIT was confirmed using Bayesian estimates of the effect sizes, which are more accurate and interpretable than conventional effect sizes. Moreover, hierarchical Bayesian modeling provided information that is not available from the conventional statistical analysis procedure.



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Assessment of the implant geometry in fractionated interstitial HDR breast brachytherapy using an electromagnetic tracking system

Publication date: Available online 13 November 2017
Source:Brachytherapy
Author(s): Markus Kellermeier, Rainer Fietkau, Vratislav Strnad, Christoph Bert
PurposeDuring the partial-breast treatment course by interstitial brachytherapy, electromagnetic tracking (EMT) was applied to measure the implant geometry. Implant-geometry variation, choice of reference data, and three registration methods were assessed.Methods and materialsThe implant geometry was measured in 28 patients after catheter implantation (EMTbed), during CT imaging (EMTCT), and in each of up to n = 9 treatment fractions (EMTF(k), k = 1, 2,… n). EMTF(k) were registered to the planned implant reconstruction (CTplan) by using all dwell positions (DPs), the button centers, or three fiducial sensors on the patient's skin. Variation in implant geometry obtained from EMTF(k) was assessed for EMTbed, EMTCT, and CTplan.ResultsEMT was used to measure 3932 catheters. A duration of 6.5 ± 1.7 min was needed for each implant measurement (mean, 17 catheters) plus setup of the EMT system. Data registration based on the DP deviated significantly lower than registration on button centers or fiducial sensors. Within a registration group, there was a <0.5-mm difference in the choice of reference data. Using CTplan as reference for registration, the mean residual distance of DPs on EMT-derived DPs was found at 2.1 ± 1.6 mm (EMTbed), 1.3 ± 0.9 mm (EMTCT), and 2.5 ± 1.5 mm (EMTF(k)).ConclusionsEMT can assess the implant geometry in high-dose-rate interstitial brachytherapy breast treatments. EMTbed, EMTCT, and CTplan data can serve as reference for assessment of implant changes.



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A novel double-layer mucoadhesive tablet containing probiotic strain for vaginal administration: Design, development and technological evaluation

Publication date: 15 January 2018
Source:European Journal of Pharmaceutical Sciences, Volume 112
Author(s): María Teresa Sánchez, María Adolfina Ruiz, Herminia Castán, María Encarnación Morales
Vulvovaginal candidosis caused by Candida spp. is the most prevalent vaginal infection in Europe and the second one in EE.UU, so it has become a major female concern. Probiotics bacteria have been proposed as an alternative treatment with the aim of avoiding the adverse effects associated with conventional therapies including antibiotics and other aggressive drugs for the vaginal mucosa and microbiota. The purpose of this work was to design and develop a novel vaginal tablet that contained Lactobacillus spp. bacteria as a treatment against vulvovaginal infections. A total of 21 two-layers vaginal tablets, which contained different polymeric ratios, were proposed. However, formulation F4 (20mg Na-CMC; 50mg Carbopol® 934; 20mg chitosan) was selected as optimal according to its swelling index and dissolution/erosion capability. F4 tablets showed suitable technological properties for vaginal administration as well as mucoadhesion time (24.36±0.88h) and force (0.0941N). Disintegration assay in simulated vaginal fluid (SVF, pH5.5) showed that effervescent layer disappeared in 27.48±0.05s whilst matrix layer was totally gelled in 1h. Two different release profiles were achieved; on the one hand, a promptly release due to the dissolution of both effervescent layer and matrix layer's surface (1.10×10⁸CFU/g), on the second hand, a prolonged released of the remaining bacteria until 24h (5.48×10⁷CFU/g). For stability and storage study, it was found that bacteria viability was constant until 90days in both ways of storage, in a desiccator and at room temperature, with a final dosage of 10⁸CFU/g which was considered appropriate for vaginal therapy (10⁸–10¹⁰CFU/g).

Graphical abstract

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Optimal Ultrasound Criteria for Grading Stenosis of the Superficial Femoral Artery

Publication date: Available online 14 November 2017
Source:Ultrasound in Medicine & Biology
Author(s): Mingjie Gao, Yang Hua, Xinyu Zhao, Lingyun Jia, Jie Yang, Beibei Liu
This retrospective study determined the duplex ultrasound scanning criteria for detecting 50%–69% and 70%–99% stenosis of the superficial femoral artery (SFA). Examinations of 278 limbs in 185 patients with peripheral arterial disease were performed. Duplex ultrasound scanning was used to measure the diameter of the vascular lumen, the peak systolic velocity (PSV) at the stenotic segment of the SFA (PSVst), the segment proximal to the stenosis (PSVpro) and the popliteal artery (PSVpop, distal to the stenosis). The ratios PSVst/PSVpro and PSVst/PSVpop were calculated. Receiver operator characteristic curves were plotted, with digital subtraction angiography as the reference. PSVst and PSVst/PSVpop had the highest diagnostic value for stenosis. Cut-off thresholds were: for 50%–69% stenosis, PSVst ≥ 210 cm/s, PSVst/PSVpop ≥ 2.5, with PSVst the better parameter; for 70%–99% stenosis, PSVst ≥ 275 cm/s, PSVst/PSVpop ≥ 4.0, with PSVst/PSVpop superior. PSVst/PSVpop may be a better parameter than PSVst/PSVpro for diagnosing SFA stenosis.



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Development of a 3 French Dual-Frequency Intravascular Ultrasound Catheter

Publication date: Available online 14 November 2017
Source:Ultrasound in Medicine & Biology
Author(s): Chelsea E. Munding, Emmanuel Chérin, Isaac Jourard, Jill J. Weyers, David E. Goertz, Brian K. Courtney, F. Stuart Foster
Coronary plaque morphology, including plaque size and fibrous cap thickness, is thought to contribute to the risk of plaque rupture and future cardiac events. Dual-frequency intravascular ultrasound has been proposed as a possible technique to visualize both large-scale features and superficial detail of coronary plaque; however, it has not been found to be feasible within the constraints of a clinically functional intravascular ultrasound catheter. In this study, we describe the design and fabrication of a dual-frequency catheter using a bidirectional transducer stack with center frequencies of approximately 30 and 80 MHz. We describe how the high-frequency transducer achieves significantly improved axial and lateral resolution (16 and 120 µm, respectively, vs. 50 and 220 µm) at the expense of penetration depth. Finally, imaging of ex vivo human coronary artery segments reveals that the catheter can provide complementary images of the deeper arterial wall and superficial plaque features.



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Distinct TERB1 Domains Regulate Different Protein Interactions in Meiotic Telomere Movement

Publication date: 14 November 2017
Source:Cell Reports, Volume 21, Issue 7
Author(s): Jingjing Zhang, Zhaowei Tu, Yoshinori Watanabe, Hiroki Shibuya
Meiotic telomeres attach to the nuclear envelope (NE) and drive the chromosome movement required for the pairing of homologous chromosomes. The meiosis-specific telomere proteins TERB1, TERB2, and MAJIN are required to regulate these events, but their assembly processes are largely unknown. Here, we developed a germ-cell-specific knockout mouse of the canonical telomere-binding protein TRF1 and revealed an essential role for TRF1 in directing the assembly of TERB1-TERB2-MAJIN. Further, we identified a TERB2 binding (T2B) domain in TERB1 that is dispensable for the TRF1-TERB1 interaction but is essential for the subsequent TERB1-TERB2 interaction and therefore for telomere attachment to the NE. Meanwhile, cohesin recruitment at telomeres, which is required for efficient telomere movement, is mediated by the MYB-like domain of TERB1, but not by TERB2-MAJIN. Our results reveal distinct protein interactions through various domains of TERB1, which enable the sequential assembly of the meiotic telomere complex for their movements.

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Teaser

During meiosis, telomeres attach to the nuclear envelope and drive the chromosome movement required for the pairing of homologous chromosomes. Zhang et al. reveal protein interaction networks within mammalian meiotic telomere complex, mediated by various domains of TERB1, which enable the sequential assembly of the complex and subsequent telomere movements.


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CRISPR Transcriptional Activation Analysis Unmasks an Occult γ-Secretase Processivity Defect in Familial Alzheimer’s Disease Skin Fibroblasts

Publication date: 14 November 2017
Source:Cell Reports, Volume 21, Issue 7
Author(s): Keiichi Inoue, Luis M.A. Oliveira, Asa Abeliovich
Mutations in presenilin (PSEN) 1 and 2, which encode components of the γ-secretase (GS) complex, cause familial Alzheimer's disease (FAD). It is hypothesized that altered GS-mediated processing of the amyloid precursor protein (APP) to the Aβ42 fragment, which is accumulated in diseased brain, may be pathogenic. Here, we describe an in vitro model system that enables the facile analysis of neuronal disease mechanisms in non-neuronal patient cells using CRISPR gene activation of endogenous disease-relevant genes. In FAD patient-derived fibroblast cultures, CRISPR activation of APP or BACE unmasked an occult processivity defect in downstream GS-mediated carboxypeptidase cleavage of APP, ultimately leading to higher Aβ42 levels. These data suggest that, selectively in neurons, relatively high levels of BACE1 activity lead to substrate pressure on FAD-mutant GS complexes, promoting CNS Aβ42 accumulation. Our results introduce an additional platform for analysis of neurological disease.

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Teaser

Availability of facile cell-based models is a challenge in the study of neurodegenerative diseases. Using CRISPR activation, Inoue et al. demonstrate that activation of the APP and/or BACE1 genes unmasks a γ-secretase carboxypeptidase deficiency in patient fibroblasts, promoting Aβ42 accumulation.


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High-Throughput Drug Screening Identifies Pazopanib and Clofilium Tosylate as Promising Treatments for Malignant Rhabdoid Tumors

Publication date: 14 November 2017
Source:Cell Reports, Volume 21, Issue 7
Author(s): Céline Chauvin, Amaury Leruste, Arnault Tauziede-Espariat, Mamy Andrianteranagna, Didier Surdez, Aurianne Lescure, Zhi-Yan Han, Elodie Anthony, Wilfrid Richer, Sylvain Baulande, Mylène Bohec, Sakina Zaidi, Marie-Ming Aynaud, Laetitia Maillot, Julien Masliah-Planchon, Stefano Cairo, Sergio Roman-Roman, Olivier Delattre, Elaine Del Nery, Franck Bourdeaut
Rhabdoid tumors (RTs) are aggressive tumors of early childhood characterized by SMARCB1 inactivation. Their poor prognosis highlights an urgent need to develop new therapies. Here, we performed a high-throughput screening of approved drugs and identified broad inhibitors of tyrosine kinase receptors (RTKs), including pazopanib, and the potassium channel inhibitor clofilium tosylate (CfT), as SMARCB1-dependent candidates. Pazopanib targets were identified as PDGFRα/β and FGFR2, which were the most highly expressed RTKs in a set of primary tumors. Combined genetic inhibition of both these RTKs only partially recapitulated the effect of pazopanib, emphasizing the requirement for broad inhibition. CfT perturbed protein metabolism and endoplasmic reticulum stress and, in combination with pazopanib, induced apoptosis of RT cells in vitro. In vivo, reduction of tumor growth by pazopanib was enhanced in combination with CfT, matching the efficiency of conventional chemotherapy. These results strongly support testing pazopanib/CfT combination therapy in future clinical trials for RTs.

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Teaser

Rhabdoid tumors (RTs) are aggressive pediatric tumors characterized by SMARCB1 inactivation. Chauvin et al. identify two SMARCB1-dependent targeted therapies for RT: pazopanib, which inhibits PDGFR and FGFR2, and the potassium channel inhibitor clofilium tosylate, which induces endoplasmic reticulum stress. Combining both drugs induces cell apoptosis and reduces PDX tumor growth.


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PfClpC Is an Essential Clp Chaperone Required for Plastid Integrity and Clp Protease Stability in Plasmodium falciparum

Publication date: 14 November 2017
Source:Cell Reports, Volume 21, Issue 7
Author(s): Anat Florentin, David W. Cobb, Jillian D. Fishburn, Michael J. Cipriano, Paul S. Kim, Manuel A. Fierro, Boris Striepen, Vasant Muralidharan
The deadly malaria parasite Plasmodium falciparum contains a nonphotosynthetic plastid, known as the apicoplast, that functions to produce essential metabolites, and drugs that target the apicoplast are clinically effective. Several prokaryotic caseinolytic protease (Clp) genes have been identified in the Plasmodium genome. Using phylogenetic analysis, we focused on the Clp members that may form a regulated proteolytic complex in the apicoplast. We genetically targeted members of this complex and generated conditional mutants of the apicoplast-localized PfClpC chaperone and PfClpP protease. Conditional inhibition of the PfClpC chaperone resulted in growth arrest and apicoplast loss and was rescued by addition of the essential apicoplast-derived metabolite IPP. Using a double-conditional mutant parasite line, we discovered that the chaperone activity is required to stabilize the mature protease, revealing functional interactions. These data demonstrate the essential function of PfClpC in maintaining apicoplast integrity and its role in regulating the proteolytic activity of the Clp complex.

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Teaser

Plasmodium falciparum contains a unique organelle, the apicoplast. Using genetic and phenotypic assays, Florentin et al. characterize the apicoplast Clp chaperone and protease. They find that the chaperone is essential for protease stability and that together they function to maintain organelle integrity and segregation into daughter cells.


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Lateral Preoptic Control of the Lateral Habenula through Convergent Glutamate and GABA Transmission

Publication date: 14 November 2017
Source:Cell Reports, Volume 21, Issue 7
Author(s): David J. Barker, Jorge Miranda-Barrientos, Shiliang Zhang, David H. Root, Hui-Ling Wang, Bing Liu, Erin S. Calipari, Marisela Morales
The lateral habenula (LHb) is a brain structure that participates in cognitive and emotional processing and has been implicated in several mental disorders. Although one of the largest inputs to the LHb originates in the lateral preoptic area (LPO), little is known about how the LPO participates in the regulation of LHb function. Here, we provide evidence that the LPO exerts bivalent control over the LHb through the convergent transmission of LPO glutamate and γ-aminobutyric acid (GABA) onto single LHb neurons. In vivo, both LPO-glutamatergic and LPO-GABAergic inputs to the LHb are activated by aversive stimuli, and their predictive cues yet produce opposing behaviors when stimulated independently. These results support a model wherein the balanced response of converging LPO-glutamate and LPO-GABA are necessary for a normal response to noxious stimuli, and an imbalance in LPO→LHb glutamate or GABA results in the type of aberrant processing that may underlie mental disorders.

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Teaser

Barker et al. show that distinct populations of lateral preoptic area glutamate and GABA neurons synapse together on single lateral habenula neurons and find that this "convergent neurotransmission" allows preoptic area neurons to exert bivalent control over single lateral habenula neurons and drive opposing motivational states.


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Role of the Pif1-PCNA Complex in Pol δ-Dependent Strand Displacement DNA Synthesis and Break-Induced Replication

Publication date: 14 November 2017
Source:Cell Reports, Volume 21, Issue 7
Author(s): Olga Buzovetsky, Youngho Kwon, Nhung Tuyet Pham, Claire Kim, Grzegorz Ira, Patrick Sung, Yong Xiong
The S. cerevisiae Pif1 helicase functions with DNA polymerase (Pol) δ in DNA synthesis during break-induced replication (BIR), a conserved pathway responsible for replication fork repair and telomere recombination. Pif1 interacts with the DNA polymerase processivity clamp PCNA, but the functional significance of the Pif1-PCNA complex remains to be elucidated. Here, we solve the crystal structure of PCNA in complex with a non-canonical PCNA-interacting motif in Pif1. The structure guides the construction of a Pif1 mutant that is deficient in PCNA interaction. This mutation impairs the ability of Pif1 to enhance DNA strand displacement synthesis by Pol δ in vitro and also the efficiency of BIR in cells. These results provide insights into the role of the Pif1-PCNA-Pol δ ensemble during DNA break repair by homologous recombination.

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Teaser

The Pif1-PCNA-Pol δ complex plays an important role in DNA repair through break-induced replication. Buzovetsky et al. determine the crystal structure of a non-canonical PCNA-binding motif in Pif1 bound to PCNA. Biochemical and genetic analysis reveal that the Pif1-PCNA complex enhances Pol δ-mediated DNA synthesis.


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A Central Amygdala-Substantia Innominata Neural Circuitry Encodes Aversive Reinforcement Signals

Publication date: 14 November 2017
Source:Cell Reports, Volume 21, Issue 7
Author(s): Yuting Cui, Guanghui Lv, Sen Jin, Jie Peng, Jing Yuan, Xiaobin He, Hui Gong, Fuqiang Xu, Tonghui Xu, Haohong Li
Aversive stimuli can impact motivation and support associative learning as reinforcers. However, the neural circuitry underlying the processing of aversive reinforcers has not been elucidated. Here, we report that a subpopulation of central amygdala (CeA) GABAergic neurons expressing protein kinase C-delta (PKC-δ+) displays robust responses to aversive stimuli during negative reinforcement learning. Importantly, projections from PKC-δ+ neurons of the CeA to the substantia innominata (SI) could bi-directionally modulate negative reinforcement learning. Moreover, consistent with the idea that SI-projecting PKC-δ+ neurons of the CeA encode aversive information, optogenetic activation of this pathway produces conditioned place aversion, a behavior prevented by simultaneous ablating of SI glutamatergic neurons. Taken together, our data define a cell-type-specific neural circuitry modulating associative learning by encoding aversive reinforcement signals.

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Teaser

Cui et al. show that central amygdala PKC-δ+ neurons can modulate negative reinforcement learning by transmitting aversive signals to the substantia innominata.


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CPEB2 Activates GRASP1 mRNA Translation and Promotes AMPA Receptor Surface Expression, Long-Term Potentiation, and Memory

Publication date: 14 November 2017
Source:Cell Reports, Volume 21, Issue 7
Author(s): Wen-Hsin Lu, Nai-Hsing Yeh, Yi-Shuian Huang
Activity-dependent synthesis of plasticity-related proteins is necessary to sustain long-lasting synaptic modifications and consolidate memory. We investigated the role of the translational regulator cytoplasmic polyadenylation element binding protein 2 (CPEB2) in learning and memory because regulated mRNA translation contributes to synaptic plasticity. Forebrain-restricted CPEB2 conditional knockout (cKO) mice exhibited impaired hippocampus-dependent memory in contextual fear conditioning and Morris water maze tests. CPEB2 cKO hippocampi showed impaired long-term potentiation in the Schaffer collateral-CA1 pathway. Reduced surface, but not total, expression of AMPA receptors (AMPARs) in CPEB2 KO neurons led us to identify that CPEB2 enhanced the translation of GRASP1 mRNA to facilitate recycling and maintain the surface level of AMPARs. Ectopic expression of CPEB2 or GRASP1 in CA1 areas of CPEB2 cKO mouse hippocampi rescued long-term potentiation and spatial memory in a water maze test. Thus, CPEB2-regulated GRASP1 mRNA translation is pivotal for AMPAR recycling, long-term plasticity, and memory.

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Teaser

Lu et al. report that forebrain-specific deletion of CPEB2 in mice impaired hippocampus-dependent synaptic plasticity and long-term memory. CPEB2 activated GRASP1 mRNA translation to support AMPA receptor recycling and surface expression. Ectopic expression of CPEB2 or GRASP1 in hippocampal CA1 neurons sufficiently rescued memory loss.


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Partitioning of One-Carbon Units in Folate and Methionine Metabolism Is Essential for Neural Tube Closure

Publication date: 14 November 2017
Source:Cell Reports, Volume 21, Issue 7
Author(s): Kit-Yi Leung, Yun Jin Pai, Qiuying Chen, Chloe Santos, Enrica Calvani, Sonia Sudiwala, Dawn Savery, Markus Ralser, Steven S. Gross, Andrew J. Copp, Nicholas D.E. Greene
Abnormal folate one-carbon metabolism (FOCM) is implicated in neural tube defects (NTDs), severe malformations of the nervous system. MTHFR mediates unidirectional transfer of methyl groups from the folate cycle to the methionine cycle and, therefore, represents a key nexus in partitioning one-carbon units between FOCM functional outputs. Methionine cycle inhibitors prevent neural tube closure in mouse embryos. Similarly, the inability to use glycine as a one-carbon donor to the folate cycle causes NTDs in glycine decarboxylase (Gldc)-deficient embryos. However, analysis of Mthfr-null mouse embryos shows that neither S-adenosylmethionine abundance nor neural tube closure depend on one-carbon units derived from embryonic or maternal folate cycles. Mthfr deletion or methionine treatment prevents NTDs in Gldc-null embryos by retention of one-carbon units within the folate cycle. Overall, neural tube closure depends on the activity of both the methionine and folate cycles, but transfer of one-carbon units between the cycles is not necessary.

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Teaser

Leung at al. find that embryonic neural tube closure depends both on the supply of one-carbon units to the folate cycle from glycine cleavage and on the methionine cycle. In contrast, transfer of one-carbon units from the folate cycle to the methionine cycle by MTHFR is dispensable.


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Octopamine Drives Endurance Exercise Adaptations in Drosophila

Publication date: 14 November 2017
Source:Cell Reports, Volume 21, Issue 7
Author(s): Alyson Sujkowski, Divya Ramesh, Axel Brockmann, Robert Wessells
Endurance exercise is an effective therapeutic intervention with substantial pro-healthspan effects. Male Drosophila respond to a ramped daily program of exercise by inducing conserved physiological responses similar to those seen in mice and humans. Female flies respond to an exercise stimulus but do not experience the adaptive training response seen in males. Here, we use female flies as a model to demonstrate that differences in exercise response are mediated by differences in neuronal activity. The activity of octopaminergic neurons is specifically required to induce the conserved cellular and physiological changes seen following endurance training. Furthermore, either intermittent, scheduled activation of octopaminergic neurons or octopamine feeding is able to fully substitute for exercise, conferring a suite of pro-healthspan benefits to sedentary Drosophila. These experiments indicate that octopamine is a critical mediator of adaptation to endurance exercise in Drosophila.

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Teaser

Chronic exercise causes stereotypical adaptations in muscle and adipose tissue of Drosophila. Sujkowski et al. show that these adaptations require the activity of octopaminergic neurons. Differences in octopaminergic activity control sexual dimorphism in exercise response. Both octopamine feeding and stimulation of octopaminergic neurons can substitute for endurance exercise.


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Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells

Publication date: 14 November 2017
Source:Cell Reports, Volume 21, Issue 7
Author(s): Kayo Ikeda, Makoto Kinoshita, Hisako Kayama, Shushi Nagamori, Pornparn Kongpracha, Eiji Umemoto, Ryu Okumura, Takashi Kurakawa, Mari Murakami, Norihisa Mikami, Yasunori Shintani, Satoko Ueno, Ayatoshi Andou, Morihiro Ito, Hideki Tsumura, Koji Yasutomo, Keiichi Ozono, Seiji Takashima, Shimon Sakaguchi, Yoshikatsu Kanai, Kiyoshi Takeda
Foxp3⁺ regulatory T (Treg) cells, which suppress immune responses, are highly proliferative in vivo. However, it remains unclear how the active replication of Treg cells is maintained in vivo. Here, we show that branched-chain amino acids (BCAAs), including isoleucine, are required for maintenance of the proliferative state of Treg cells via the amino acid transporter Slc3a2-dependent metabolic reprogramming. Mice fed BCAA-reduced diets showed decreased numbers of Foxp3⁺ Treg cells with defective in vivo proliferative capacity. Mice lacking Slc3a2 specifically in Foxp3⁺ Treg cells showed impaired in vivo replication and decreased numbers of Treg cells. Slc3a2-deficient Treg cells showed impaired isoleucine-induced activation of the mTORC1 pathway and an altered metabolic state. Slc3a2 mutant mice did not show an isoleucine-induced increase of Treg cells in vivo and exhibited multi-organ inflammation. Taken together, these findings demonstrate that BCAA controls Treg cell maintenance via Slc3a2-dependent metabolic regulation.

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Teaser

Treg cells regulate excess immune responses and are highly proliferative in vivo. Ikeda et al. find that branched-chain amino acids (BCAAs) are essentially required to maintain expansion and the suppressive capacity of Treg cells via Slc3a2 and mTORC1.


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Th1-like Plasmodium-Specific Memory CD4+ T Cells Support Humoral Immunity

Publication date: 14 November 2017
Source:Cell Reports, Volume 21, Issue 7
Author(s): Ryan A. Zander, Rahul Vijay, Angela D. Pack, Jenna J. Guthmiller, Amy C. Graham, Scott E. Lindner, Ashley M. Vaughan, Stefan H.I. Kappe, Noah S. Butler
Effector T cells exhibiting features of either T helper 1 (Th1) or T follicular helper (Tfh) populations are essential to control experimental Plasmodium infection and are believed to be critical for resistance to clinical malaria. To determine whether Plasmodium-specific Th1- and Tfh-like effector cells generate memory populations that contribute to protection, we developed transgenic parasites that enable high-resolution study of anti-malarial memory CD4 T cells in experimental models. We found that populations of both Th1- and Tfh-like Plasmodium-specific memory CD4 T cells persist. Unexpectedly, Th1-like memory cells exhibit phenotypic and functional features of Tfh cells during recall and provide potent B cell help and protection following transfer, characteristics that are enhanced following ligation of the T cell co-stimulatory receptor OX40. Our findings delineate critical functional attributes of Plasmodium-specific memory CD4 T cells and identify a host-specific factor that can be targeted to improve resolution of acute malaria and provide durable, long-term protection against Plasmodium parasite re-exposure.

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Th1 CD4 T cells are widely described as terminally differentiated with a relatively reduced capacity to form memory or support humoral immunity. Using experimental malaria models, Zander et al. show that potent proliferative and B cell helper activity unexpectedly resides within the Plasmodium-specific Th1-like memory CD4 T cell compartment.


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