bluuebunny/crossref_metadata_2025 huggingface dataset:
Home-based specialized palliative care in patients with advanced cancer: A systematic review
Authors: Nordly Mie , Vadstrup Eva Soelberg , Sjøgren Per , Kurita Geana Paula
Published: July 2016

Objective:

Due to an urgent need for specialized palliative care (SPC) for patients with advanced cancer, an overview of available information on organization and outcomes of home-based SPC would be valuable. Our systematic review aims to give an overview of available information on the organization and outcomes of home-based SPC for patients with advanced cancer. Outcomes related to place of death, survival time, quality of life, performance status, and symptom management are included.

Method:

A PICO process search strategy consisting of terms related to cancer, palliation, and home care was employed. The search was conducted in PubMed, EMBASE, and Cochrane from January 1, 2000, to January 27, 2015. A hand search of the reference lists of the included studies was also performed.

Results:

A total of 5 articles (out of 2080 abstracts) were selected for analysis. Three additional studies were added by the hand search. Six observational and two interventional studies were evaluated. In all of these studies, the description of the SPC service was limited to the composition of the staff—no other organizational aspects were detailed. From 44 to 90% of the patients receiving home-based SPC died at home. Studies including survival and quality of life had divergent outcomes, and overall performance status did not improve. However, symptom control did improve over time.

Significance of results:

There is a lack of controlled clinical trials and organizational descriptions regarding home-based SPC for patients with advanced cancer, resulting in poor information and a lack of evidence. Generally, home-based SPC seems to have some positive effect on pain and dyspnea, but more high-quality studies are required.
The establishment of apple orchards as temperate forest garden systems and their impact on indigenous bacterial and fungal population abundance in Southern Ontario, Canada
Authors: Wartman P.C. , Dunfield K.E. , Khosla K. , Loucks C. , Van Acker R.C. , Martin R.C.
Published: July 2016

This research investigated soil microbial abundances affected by different ground management systems in establishing apple (Malus domestica cv. Idared, M9) orchards in Ontario, Canada. Four treatments, including forest garden systems with and without compost (FGSC and FGS), and grass understory systems with and without compost (GC and G), were assessed over two establishment years for gene copy abundance of soil arbuscular mycorrhizal (AM) fungi, total fungi and total bacteria using quantitative real-time polymerase chain reactions. Time had a greater effect on all three soil microbial abundances, with total bacterial and AM fungi decreasing and total fungal abundance increasing from spring 2013 to fall 2014. The changes were greatest between the sampling dates of fall 2013 and spring 2014, which is 1 yr after the establishment of the experimental apple plots. There were no significant differences in soil microbial abundances between treatments at any specific sampling date. Apple tree trunk circumference was greatest for FGSC and FGS after 2 yr, but no significant differences in GC and G treatments. In the last sampling period, fall 2014, FGSC plots had significantly greater trunk circumferences compared with G plots. Soil chemical properties neither changed over the 2 yr, nor did they differ between treatments at any one sampling time. We conclude that the apple-based FGS treatments can benefit apple tree growth and there is a basis for future research to explore specific plant–plant, plant–microbe and microbe–microbe relations in FGSs.
The strategic use of epistemological positions in a power-laden arena: anthropological expertise in asylum cases in the UK
Authors: Hoehne Markus Virgil
Published: July 2016

This paper deals with social anthropologists serving as expert witnesses in asylum proceedings in the UK. It argues that it is not a fundamental epistemological divide, but rather massive power differentials that characterise the relationship between social anthropologists and legal practitioners in this context. Within a narrow framework provided by the law, which focuses on ‘true facts’ and ‘objective evidence’, social anthropologists have to position themselves, and they often must do so somewhere along a spectrum from positivist to post-positivist positions (regarding, for example, such concepts as ‘culture’ and ‘identity’). This, as well as their subordinate position in the context of the proceedings, sits uneasily with the professional, moral and ethical standards of their discipline. Engagement as an expert, therefore, comes with certain costs for social anthropologists that range from having to bend one's own epistemological perspective to the risk of being ‘demolished’ as an expert (and beyond) in sometimes implicitly politicised asylum decisions.
Cameroon's Lake Nyos Gas Burst: 30 Years Later
Authors: Rouwet Dmitri , Tanyileke Greg , Costa Antonio
Published: July 2016

9th Workshop of the IAVCEI-Commission on Volcanic Lakes (CVL9); Cameroon, 14–24 March 2016
How Do the Deep Waters of the Antarctic Form?
Authors: Yan Wudan
Published: July 2016

Researchers uncover new insights into the life cycle of water in the Antarctic region by measuring noble gas concentrations.
Evaluation of techniques for performing cellular isolation and preservation during microgravity conditions
Authors: Rizzardi Lindsay F , Kunz Hawley , Rubins Kathleen , Chouker Alexander , Quiriarte Heather , Sams Clarence , Crucian Brian E , Feinberg Andrew P
Published: July 2016

Genomic and epigenomic studies require the precise transfer of microliter volumes among different types of tubes in order to purify DNA, RNA, or protein from biological samples and subsequently perform analyses of DNA methylation, RNA expression, and chromatin modifications on a genome-wide scale. Epigenomic and transcriptional analyses of human blood cells, for example, require separation of purified cell types to avoid confounding contributions of altered cellular proportions, and long-term preservation of these cells requires their isolation and transfer into appropriate freezing media. There are currently no protocols for these cellular isolation procedures on the International Space Station (ISS). Currently human blood samples are either frozen as mixed cell populations (within the CPT collection tubes) with poor yield of viable cells required for cell-type isolations, or returned under ambient conditions, which requires timing with Soyuz missions. Here we evaluate the feasibility of translating terrestrial cell purification techniques to the ISS. Our evaluations were performed in microgravity conditions during parabolic atmospheric flight. The pipetting of open liquids in microgravity was evaluated using analog-blood fluids and several types of pipette hardware. The best-performing pipettors were used to evaluate the pipetting steps required for peripheral blood mononuclear cell (PBMC) isolation following terrestrial density-gradient centrifugation. Evaluation of actual blood products was performed for both the overlay of diluted blood, and the transfer of isolated PBMCs. We also validated magnetic purification of cells. We found that positive-displacement pipettors avoided air bubbles, and the tips allowed the strong surface tension of water, glycerol, and blood to maintain a patent meniscus and withstand robust pipetting in microgravity. These procedures will greatly increase the breadth of research that can be performed on board the ISS, and allow improvised experimentation by astronauts on extraterrestrial missions.
Landscape determinants of fine-scale genetic structure of a small rodent in a heterogeneous landscape (Hluhluwe-iMfolozi Park, South Africa)
Authors: Russo Isa-Rita M. , Sole Catherine L. , Barbato Mario , von Bramann Ullrich , Bruford Michael W.
Published: July 2016

Small mammals provide ecosystem services, acting, for example, as pollinators and seed dispersers. In addition, they are also disease reservoirs that can be detrimental to human health and they can also act as crop pests. Knowledge of their dispersal preferences is therefore useful for population management and landscape planning. Genetic data were used alongside landscape data to examine the influence of the landscape on the demographic connectedness of the Natal multimammate mouse (Mastomys natalensis) and to identify landscape characteristics that influence the genetic structure of this species across a spatially and temporally varying environment. The most significant landscape features shaping gene flow were aspect, vegetation cover, topographic complexity (TC) and rivers, with western facing slopes, topographic complexity and rivers restricting gene flow. In general, thicket vegetation was correlated with increased gene flow. Identifying features of the landscape that facilitate movement/dispersal in M. natalensis potentially has application for other small mammals in similar ecosystems. As the primary reservoir host of the zoonotic Lassa virus, a landscape genetics approach may have applications in determining areas of high disease risk to humans. Identifying these landscape features may also be important in crop management due to damage by rodent pests.
Beyond endoscopic assessment in inflammatory bowel disease: real-time histology of disease activity by non-linear multimodal imaging
Authors: Chernavskaia Olga , Heuke Sandro , Vieth Michael , Friedrich Oliver , Schürmann Sebastian , Atreya Raja , Stallmach Andreas , Neurath Markus F. , Waldner Maximilian , Petersen Iver , Schmitt Michael , Bocklitz Thomas , Popp Jürgen
Published: July 2016

Assessing disease activity is a prerequisite for an adequate treatment of inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis. In addition to endoscopic mucosal healing, histologic remission poses a promising end-point of IBD therapy. However, evaluating histological remission harbors the risk for complications due to the acquisition of biopsies and results in a delay of diagnosis because of tissue processing procedures. In this regard, non-linear multimodal imaging techniques might serve as an unparalleled technique that allows the real-time evaluation of microscopic IBD activity in the endoscopy unit. In this study, tissue sections were investigated using the non-linear multimodal microscopy combination of coherent anti-Stokes Raman scattering (CARS), two-photon excited auto fluorescence (TPEF) and second-harmonic generation (SHG). After the measurement a gold-standard assessment of histological indexes was carried out based on a conventional H&E stain. Subsequently, various geometry and intensity related features were extracted from the multimodal images. An optimized feature set was utilized to predict histological index levels based on a linear classifier. Based on the automated prediction, the diagnosis time interval is decreased. Therefore, non-linear multimodal imaging may provide a real-time diagnosis of IBD activity suited to assist clinical decision making within the endoscopy unit.
Influence of Metal Diboride and Dy2O3 Additions on Microstructure and Properties of MgB2 Fabricated at High Temperatures and under Pressure
Authors: Yang Y. , Sumption M. D. , Collings E. W.
Published: July 2016

High temperatures and under pressure (HTP) processing has been used to study the effects of chemical doping in MgB2. ZrB2, TiB2 and NbB2 were selected as additives since, like MgB2, they have an AlB2-type structure and similar lattice parameters. Dy2O3 was selected as it has been reported to generate nanoscale, secondary intragrain phases in MgB2. While C is known to enter the B-sublattice readily, attempts to dope Zr and other elements onto the Mg site have been less successful due to slow bulk diffusion, low solubility in MgB2, or both. We have used high-temperature, solid-state sintering (1500 °C), as well as excursions through the peritectic temperature (up to 1700 °C), to investigate both of these limitations. Bulk MgB2 samples doped with MB2 (M = Zr, Ti and Nb) and Dy2O3 additions were synthesized and then characterized. Lattice distortion and high densities of crystal defects were observed in the MgB2 grains around nano-sized MB2 inclusions, this highly defected band contributed to a large increase in Bc2 but was not large enough to increase the irreversibility field. In contrast, distributed intragrain precipitates were formed by Dy2O3 additions which did not change the lattice parameters, Tc, Tc distribution or Bc2 of MgB2, but modified the flux pinning.
Methane limit LPS-induced NF-κB/MAPKs signal in macrophages and suppress immune response in mice by enhancing PI3K/AKT/GSK-3β-mediated IL-10 expression
Authors: Zhang Xu , Li Na , Shao Han , Meng Yan , Wang Liping , Wu Qian , Yao Ying , Li Jinbao , Bian Jinjun , Zhang Yan , Deng Xiaoming
Published: July 2016

Inflammatory diseases such as sepsis and autoimmune colitis, characterized by an overwhelming activation of the immune system and the counteracting anti-inflammatory response, remain a major health problem in worldwide. Emerging evidence suggests that methane have a protective effect on many animal models, like ischaemia reperfusion injury and diabetes-associated diseases. Whether methane could modulating inflammatory diseases remains largely unknown. Here we show that methane-rich saline (MS) ip treatment (16 ml/kg) alleviated endotoxin shock, bacteria-induced sepsis and dextran-sulfate-sodium-induced colitis in mice via decreased production of TNF-α and IL-6. In MS-treated macrophages, LPS-induced activation of NF-κb/MAPKs was attenuated. Interestingly, MS treatment significantly elevated the levels of IL-10 both in vitro and in vivo. Neutralization of IL-10 abrogated the therapeutic effect of MS. Moreover, anti-IL10 blockade partially restored the MS-mediated attenuation of NF-κb/MAPKs phosphorylation. We further found that MS resulted in markedly enhanced phosphorylation of GSK-3β and AKT, which both mediate the release of Il-10. Additionally, inhibition of PI3K attenuated MS-mediated p-GSK-3β and IL-10 production and reversed the suppressed activation of NF-κb/ MAPKs in response to LPS. Our results reveal a novel effect and mechanisms of methane and support the potential value of MS as a therapeutic approach in innate inflammatory diseases.
DNA replication inhibitor hydroxyurea alters Fe-S centers by producing reactive oxygen species in vivo
Authors: Huang Meng-Er , Facca Céline , Fatmi Zakaria , Baïlle Dorothée , Bénakli Safia , Vernis Laurence
Published: July 2016

Redox homeostasis is tightly controlled in cells as it is critical for most cellular functions. Iron-Sulfur centers (Fe-S) are metallic cofactors with electronic properties that are associated with proteins and allow fine redox tuning. Following the observation that altered Fe-S biosynthesis is correlated with a high sensitivity to hydroxyurea (HU), a potent DNA replication blocking agent, we identified that oxidative stress response pathway under the control of the main regulator Yap1 attenuates HU deleterious effects, as it significantly increases resistance to HU, Fe-S biosynthesis and DNA replication kinetics in the presence of HU. Yap1 effect is mediated at least in part through up-regulation of two highly conserved genes controlling cytosolic Fe-S biosynthesis and oxidative stress, Dre2 and Tah18. We next observed that HU produces deleterious effects on cytosolic Fe-S clusters in proteins in vivo but not in vitro, suggesting that HU’s impact on Fe-S in vivo is mediated by cellular metabolism. Finally, we evidenced that HU exposure was accompanied by production of reactive oxygen species intracellularly. Altogether, this study provides mechanistic insight on the initial observation that mutants with altered Fe-S biosynthesis are highly sensitive to HU and uncovers a novel mechanism of action of this widely used DNA replication inhibitor.
Deciphering the function of the CNGB1b subunit in olfactory CNG channels
Authors: Nache Vasilica , Wongsamitkul Nisa , Kusch Jana , Zimmer Thomas , Schwede Frank , Benndorf Klaus
Published: July 2016

Olfactory cyclic nucleotide-gated (CNG) ion channels are key players in the signal transduction cascade of olfactory sensory neurons. The second messengers cAMP and cGMP directly activate these channels, generating a depolarizing receptor potential. Olfactory CNG channels are composed of two CNGA2 subunits and two modulatory subunits, CNGA4, and CNGB1b. So far the exact role of the modulatory subunits for channel activation is not fully understood. By measuring ligand binding and channel activation simultaneously, we show that in functional heterotetrameric channels not only the CNGA2 subunits and the CNGA4 subunit but also the CNGB1b subunit binds cyclic nucleotides and, moreover, also alone translates this signal to open the pore. In addition, we show that the CNGB1b subunit is the most sensitive subunit in a heterotetrameric channel to cyclic nucleotides and that it accelerates deactivation to a similar extent as does the CNGA4 subunit. In conclusion, the CNGB1b subunit participates in ligand-gated activation of olfactory CNG channels and, particularly, contributes to rapid termination of odorant signal in an olfactory sensory neuron.
Uncertainty analysis for an effluent trading system in a typical nonpoint-sources-polluted watershed
Authors: Chen Lei , Han Zhaoxing , Wang Guobo , Shen Zhenyao
Published: July 2016

Conventional effluent trading systems (ETSs) between point sources (PSs) and nonpoint sources (NPSs) are often unreliable because of the uncertain characteristics of NPSs. In this study, a new framework was established for PS-NPS ETSs, and a comprehensive analysis was conducted by quantifying the impacts of the uncertainties associated with the water assimilative capacity (WAC), NPS emissions, and measurement effectiveness. On the basis of these results, the uncertain characteristics of NPSs would result in a less cost-effective PS-NPS ETS during most hydrological periods, and there exists a clear transition occurs from the WAC constraint to the water quality constraint if these stochastic factors are considered. Specifically, the emission uncertainty had a greater impact on PSs, but an increase in the emission or abatement uncertainty caused the abatement efforts to shift from NPSs toward PSs. Moreover, the error transitivity from the WAC to conventional ETS approaches is more obvious than that to the WEFZ-based ETS. When NPSs emissions are relatively high, structural BMPs should be considered for trading, and vice versa. These results are critical to understand the impacts of uncertainty on the functionality of PS-NPS ETSs and to provide a trade-off between the confidence level and abatement efforts.
3′-UTR engineering to improve soluble expression and fine-tuning of activity of cascade enzymes in Escherichia coli
Authors: Song Ji-Won , Woo Ji-Min , Jung Gyoo Yeol , Bornscheuer Uwe T. , Park Jin-Byung
Published: July 2016

3′-Untranslated region (3′UTR) engineering was investigated to improve solubility of heterologous proteins (e.g., Baeyer-Villiger monooxygenases (BVMOs)) in Escherichia coli. Insertion of gene fragments containing putative RNase E recognition sites into the 3′UTR of the BVMO genes led to the reduction of mRNA levels in E. coli. Importantly, the amounts of soluble BVMOs were remarkably enhanced resulting in a proportional increase of in vivo catalytic activities. Notably, this increase in biocatalytic activity correlated to the number of putative RNase E endonucleolytic cleavage sites in the 3′UTR. For instance, the biotransformation activity of the BVMO BmoF1 (from Pseudomonas fluorescens DSM50106) in E. coli was linear to the number of RNase E cleavage sites in the 3′UTR. In summary, 3′UTR engineering can be used to improve the soluble expression of heterologous enzymes, thereby fine-tuning the enzyme activity in microbial cells.
CHIP−/−-Mouse Liver: Adiponectin-AMPK-FOXO-Activation Overrides CYP2E1-Elicited JNK1-Activation, Delaying Onset of NASH: Therapeutic Implications
Authors: Kim Sung-Mi , Grenert James P. , Patterson Cam , Correia Maria Almira
Published: July 2016

Genetic ablation of C-terminus of Hsc70-interacting protein (CHIP) E3 ubiquitin-ligase impairs hepatic cytochrome P450 CYP2E1 degradation. Consequent CYP2E1 gain of function accelerates reactive O2 species (ROS) production, triggering oxidative/proteotoxic stress associated with sustained activation of c-Jun NH2-terminal kinase (JNK)-signaling cascades, pro-inflammatory effectors/cytokines, insulin resistance, progressive hepatocellular ballooning and microvesicular steatosis. Despite this, little evidence of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) was found in CHIP−/−-mice over the first 8–9-months of life. We herein document that this lack of tissue injury is largely due to the concurrent up-regulation and/or activation of the adiponectin-5′-AMP-activated protein kinase (AMPK)-forkhead box O (FOXO)-signaling axis stemming from at the least three synergistic features: Up-regulated expression of adipose tissue adiponectin and its hepatic adipoR1/adipoR2 receptors, stabilization of hepatic AMPKα1-isoform, identified herein for the first time as a CHIP-ubiquitination substrate (unlike its AMPKα2-isoform), as well as nuclear stabilization of FOXOs, well-known CHIP-ubiquitination targets. Such beneficial predominance of the adiponectin-AMPK-FOXO-signaling axis over the sustained JNK-elevation and injurious insulin resistance in CHIP−/−-livers apparently counteracts/delays rapid progression of the hepatic microvesicular steatosis to the characteristic macrovesicular steatosis observed in clinical NASH and/or rodent NASH-models.
Complete Genome Analysis of an Enterovirus EV-B83 Isolated in China
Authors: Tang Jingjing , Li Qiongfen , Tian Bingjun , Zhang Jie , Li Kai , Ding Zhengrong , Lu Lin
Published: July 2016

Enterovirus B83 (EV-B83) is a recently identified member of enterovirus species B. It is a rarely reported serotype and up to date, only the complete genome sequence of the prototype strain from the United States is available. In this study, we describe the complete genomic characterization of an EV-B83 strain 246/YN/CHN/08HC isolated from a healthy child living in border region of Yunnan Province, China in 2008. Compared with the prototype strain, it had 79.6% similarity in the complete genome and 78.9% similarity in the VP1 coding region, reflecting the great genetic divergence among them. VP1-coding region alignment revealed it had 77.2–91.3% with other EV-B83 sequences available in GenBank. Similarity plot analysis revealed it had higher identity with several other EV-B serotypes than the EV-B83 prototype strain in the P2 and P3 coding region, suggesting multiple recombination events might have occurred. The great genetic divergence with previously isolated strains and the extremely rare isolation suggest this serotype has circulated at a low epidemic strength for many years. This is the first report of complete genome of EV-B83 in China.
Post-exposure treatment with whole inactivated H5N1 avian influenza virus protects against lethal homologous virus infection in mice
Authors: Hagan Mable , Ranadheera Charlene , Audet Jonathan , Morin Jocelyn , Leung Anders , Kobasa Darwyn
Published: July 2016

Concerns with H5N1 influenza viruses include their prevalence in wild and domestic poultry, high mortality rate (~60%) in humans with some strains, lack of pre-existing immunity in humans and the possibility that these viruses acquire mutations that enable efficient transmission between humans. H5 subtype viruses of Eurasian origin have recently appeared in wild and domestic bird populations in North America and have led to the generation of new virus strains that are highly pathogenic in poultry. These new H5 HA containing viruses with their ability to evolve rapidly represent an unknown threat to humans in contact with infected poultry and vaccination with an off-the-shelf vaccine may be impractical to provide protection to at-risk individuals. Instead, we have evaluated the efficacy of a formalin-inactivated vaccine, which could be derived directly from a circulating virus, to provide post-exposure protection. This strategy was evaluated using a prototypic highly pathogenic avian H5N1 strain, A/Vietnam/1203/2004 and demonstrated rapid induction of adaptive immune responses providing protection in a mammalian model of lethal infection. Additionally, this post-exposure vaccine was highly efficacious when administered 24 hours after exposure. This study offers a platform for developing effective post-exposure vaccines for treatment of highly virulent influenza infections.
Exploration of acetanilide derivatives of 1-(ω-phenoxyalkyl)uracils as novel inhibitors of Hepatitis C Virus replication
Authors: Magri Andrea , Ozerov Alexander A. , Tunitskaya Vera L. , Valuev-Elliston Vladimir T. , Wahid Ahmed , Pirisi Mario , Simmonds Peter , Ivanov Alexander V. , Novikov Mikhail S. , Patel Arvind H.
Published: July 2016

Hepatitis C Virus (HCV) is a major public health problem worldwide. While highly efficacious directly-acting antiviral agents have been developed in recent years, their high costs and relative inaccessibility make their use limited. Here, we describe new 1-(ω-phenoxyalkyl)uracils bearing acetanilide fragment in 3 position of pyrimidine ring as potential antiviral drugs against HCV. Using a combination of various biochemical assays and in vitro virus infection and replication models, we show that our compounds are able to significantly reduce viral genomic replication, independently of virus genotype, with their IC50 values in the nanomolar range. We also demonstrate that our compounds can block de novo RNA synthesis and that effect is dependent on a chemical structure of the compounds. A detailed structure-activity relationship revealed that the most active compounds were the N3-substituted uracil derivatives containing 6-(4-bromophenoxy)hexyl or 8-(4-bromophenoxy)octyl fragment at N1 position.
Imaging cervical cytology with scanning near-field optical microscopy (SNOM) coupled with an IR-FEL
Authors: Halliwell Diane E. , Morais Camilo L. M. , Lima Kássio M. G. , Trevisan Julio , Siggel-King Michele R. F. , Craig Tim , Ingham James , Martin David S. , Heys Kelly A. , Kyrgiou Maria , Mitra Anita , Paraskevaidis Evangelos , Theophilou Georgios , Martin-Hirsch Pierre L. , Cricenti Antonio , Luce Marco , Weightman Peter , Martin Francis L.
Published: July 2016

Cervical cancer remains a major cause of morbidity and mortality among women, especially in the developing world. Increased synthesis of proteins, lipids and nucleic acids is a pre-condition for the rapid proliferation of cancer cells. We show that scanning near-field optical microscopy, in combination with an infrared free electron laser (SNOM-IR-FEL), is able to distinguish between normal and squamous low-grade and high-grade dyskaryosis and between normal and mixed squamous/glandular pre-invasive and adenocarcinoma cervical lesions, at designated wavelengths associated with DNA, Amide I/II and lipids. These findings evidence the promise of the SNOM-IR-FEL technique in obtaining chemical information relevant to the detection of cervical cell abnormalities and cancer diagnosis at spatial resolutions below the diffraction limit (≥0.2 μm). We compare these results with analyses following attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy; although this latter approach has been demonstrated to detect underlying cervical atypia missed by conventional cytology, it is limited by a spatial resolution of ~3 μm to 30 μm due to the optical diffraction limit.
Therapeutic targeting of myeloid-derived suppressor cells involves a novel mechanism mediated by clusterin
Authors: Zhou Junmin , Donatelli Sarah S. , Gilvary Danielle L. , Tejera Melba M. , Eksioglu Erika A. , Chen Xianghong , Coppola Domenico , Wei Sheng , Djeu Julie Y.
Published: July 2016

Myeloid-derived suppressor cells (MDSCs) constitute a key checkpoint that impedes tumor immunity against cancer. Chemotherapeutic intervention of MDSCs has gained ground as a strategy for cancer therapy but its mechanism remains obscure.We report here a unique mechanism by which monocytic (M)-MDSCs are spared, allowing them to polarize towards M1 macrophages for reactivation of immunity against breast cancer. We first demonstrated that curcumin, like docetaxel (DTX), can selectively target CD11b+Ly6G+Ly6Clow granulocytic (G)-MDSCs, sparing CD11b+Ly6G−Ly6Chigh M-MDSCs, with reduced tumor burden in 4T1-Neu tumor-bearing mice. Curcumin treatment polarized surviving M-MDSCs toward CCR7+ Dectin-1−M1 cells, accompanied by IFN-γ production and cytolytic function in T cells. Selective M-MDSC chemoresistence to curcumin and DTX was mediated by secretory/cytoplasmic clusterin (sCLU). sCLU functions by trapping Bax from mitochondrial translocation, preventing the apoptotic cascade. Importantly, sCLU was only found in M-MDSCs but not in G-MDSCs. Knockdown of sCLU in M-MDSCs and RAW264.7 macrophages was found to reverse their natural chemoresistance. Clinically, breast cancer patients possess sCLU expression only in mature CD68+ macrophages but not in immature CD33+ immunosuppressive myeloid cells infiltrating the tumors. We thus made the seminal discovery that sCLU expression in M-MDSCs accounts for positive immunomodulation by chemotherapeutic agents.
Functional conservation and diversification of the soybean maturity gene E1 and its homologs in legumes
Authors: Zhang Xingzheng , Zhai Hong , Wang Yaying , Tian Xiaojie , Zhang Yupeng , Wu Hongyan , Lü Shixiang , Yang Guang , Li Yuqiu , Wang Lu , Hu Bo , Bu Qingyun , Xia Zhengjun
Published: July 2016

Gene regulatory networks involved in flowering time and photoperiodic responses in legumes remain unknown. Although the major maturity gene E1 has been successfully deciphered in soybean, knowledge on the functional conservation of this gene is limited to a certain extent to E1 homologs in legumes. The ectopic expression of Phvul.009G204600 (PvE1L), an E1 homolog from common bean, delayed the onset of flowering in soybean. By contrast, the ectopic expression of Medtr2g058520 (MtE1L) from Medicago truncatula did not affect the flowering of soybean. Characterization of the late-flowering mte1l mutant indicated that MtE1L promoted flowering in Medicago truncatula. Moreover, all transgenic E1, PvE1L and MtE1L soybean lines exhibited phenotypic changes in terms of plant height. Transgenic E1 or PvE1L plants were taller than the wild-type, whereas transgenic MtE1L plants produced dwarf phenotype with few nodes and short internode. Thus, functional conservation and diversification of E1 family genes from legumes in the regulation of flowering and plant growth may be associated with lineage specification and genomic duplication.
Breast reconstruction with single-pedicle TRAM flap in breast cancer patients with low midline abdominal scar
Authors: Wu Jun-Dong , Huang Wen-He , Qiu Si-Qi , He Li-Fang , Guo Cui-Ping , Zhang Yong-Qu , Zhang Fan , Zhang Guo-Jun
Published: July 2016

Breast reconstruction with transverse rectus abdominis myocutaneous (TRAM) flap is challenging in patients with low midline abdominal scar. In this study, we aimed to investigate the clinical feasibility of immediate breast reconstruction using single-pedicle TRAM (SP-TRAM) flaps in patients with low midline abdominal scar. There were 4 strict selection criteria: 1) presence at least 3 perforators on the pedicle side; 2) perforators with regional average flow velocity of >20 cm/s; 3) upper edge of the abdominal scar at least 4 cm from the umbilicus; and 4) scar age >1 year. Eight breast cancer patients with low midline abdominal scar (scar group) and 20 without (control group) underwent immediate breast reconstruction with SP-TRAM flaps consisting of zone I and III and zone II tissues. Flap complications, donor-site complications, and cosmetic results were compared between the two groups. All flaps survived and both groups presented similar flap and donor site complications, including fat necrosis, seroma, hematoma, infection, delayed wound healing, and abdominal hernia, and patients in both groups had similar aesthetic results (p > 0.05). Thus, the study demonstrated that breast reconstruction using SP-TRAM flap was a safe approach in carefully selected patients with low midline abdominal scar.
Advances in mapping malaria for elimination: fine resolution modelling of Plasmodium falciparum incidence
Authors: Alegana Victor A. , Atkinson Peter M. , Lourenço Christopher , Ruktanonchai Nick W. , Bosco Claudio , Erbach-Schoenberg Elisabeth zu , Didier Bradley , Pindolia Deepa , Le Menach Arnaud , Katokele Stark , Uusiku Petrina , Tatem Andrew J.
Published: July 2016

The long-term goal of the global effort to tackle malaria is national and regional elimination and eventually eradication. Fine scale multi-temporal mapping in low malaria transmission settings remains a challenge and the World Health Organisation propose use of surveillance in elimination settings. Here, we show how malaria incidence can be modelled at a fine spatial and temporal resolution from health facility data to help focus surveillance and control to population not attending health facilities. Using Namibia as a case study, we predicted the incidence of malaria, via a Bayesian spatio-temporal model, at a fine spatial resolution from parasitologically confirmed malaria cases and incorporated metrics on healthcare use as well as measures of uncertainty associated with incidence predictions. We then combined the incidence estimates with population maps to estimate clinical burdens and show the benefits of such mapping to identifying areas and seasons that can be targeted for improved surveillance and interventions. Fine spatial resolution maps produced using this approach were then used to target resources to specific local populations, and to specific months of the season. This remote targeting can be especially effective where the population distribution is sparse and further surveillance can be limited to specific local areas.
Targeting cellular mRNAs translation by CRISPR-Cas9
Authors: Liu Yuchen , Chen Zhicong , He Anbang , Zhan Yonghao , Li Jianfa , Liu Li , Wu Hanwei , Zhuang Chengle , Lin Junhao , Zhang Qiaoxia , Huang Weiren
Published: July 2016

Recently CRISPR-Cas9 system has been reported to be capable of targeting a viral RNA and this phenomenon thus raises an interesting question of whether Cas9 can also influence translation of cellular mRNAs. Here, we show that both natural and catalytically dead Cas9 can repress mRNA translation of cellular genes and that only the first 14 nt in the 5′ end of sgRNA is essential for this process. CRISPR-Cas9 can suppress the protein expression of an unintended target gene without affecting its DNA sequence and causes unexpected phenotypic changes. Using the designed RNA aptamer-ligand complexes which physically obstruct translation machinery, we indicate that roadblock mechanism is responsible for this phenomenon. Our work suggests that studies on Cas9 should avoid the potential off-target effects by detecting the alteration of genes at both the DNA and protein levels.
Orchestration of gene expression across the seasons: Hypothalamic gene expression in natural photoperiod throughout the year in the Siberian hamster
Authors: Petri Ines , Diedrich Victoria , Wilson Dana , Fernández-Calleja José , Herwig Annika , Steinlechner Stephan , Barrett Perry
Published: July 2016

In nature Siberian hamsters utilize the decrement in day length following the summer solstice to implement physiological adaptations in anticipation of the forthcoming winter, but also exploit an intrinsic interval timer to initiate physiological recrudescence following the winter solstice. However, information is lacking on the temporal dynamics in natural photoperiod of photoperiodically regulated genes and their relationship to physiological adaptations. To address this, male Siberian hamsters born and maintained outdoors were sampled every month over the course of one year. As key elements of the response to photoperiod, thyroid hormone signalling components were assessed in the hypothalamus. From maximum around the summer solstice (late-June), Dio2 expression rapidly declined in advance of physiological adaptations. This was followed by a rapid increase in Mct8 expression (T3/T4 transport), peaking early-September before gradually declining to minimum expression by the following June. Dio3 showed a transient peak of expression beginning late-August. A recrudescence of testes and body mass occurred from mid-February, but Dio2 expression remained low until late-April of the following year, converging with the time of year when responsiveness to short-day length is re-established. Other photoperiodically regulated genes show temporal regulation, but of note is a transient peak in Gpr50 around late-July.
An investigation of BMP-7 mediated alterations to BMP signalling components in human tenocyte-like cells
Authors: Klatte-Schulz Franka , Giese Gerry , Differ Christopher , Minkwitz Susann , Ruschke Karen , Puts Regina , Knaus Petra , Wildemann Britt
Published: July 2016

The incidence of tendon re-tears post-surgery is an ever present complication. It is suggested that the application of biological factors, such as bone morphogenetic protein 7 (BMP-7), can reduce complication rates by promoting tenogenic characteristics in in vitro studies. However, there remains a dearth of information in regards to the mechanisms of BMP-7 signalling in tenocytes. Using primary human tenocyte-like cells (hTLCs) from the supraspinatus tendon the BMP-7 signalling pathway was investigated: induction of the BMP associated Smad pathway and non-Smad pathways (AKT, p38, ERK1/2 and JNK); alterations in gene expression of BMP-7 associated receptors, Smad pathway components, Smad target gene (ID1) and tenogenic marker scleraxis. BMP-7 increases the expression of specific BMP associated receptors, BMPR-Ib and BMPR-II and Smad8. Additionally, BMP-7 activates significantly Smad1/5/8 and slightly p38 pathways as indicated by an increase in phosphorylation and proven by inhibition experiments, where p-ERK1/2 and p-JNK pathways remain mainly unresponsive. Furthermore, BMP-7 increases the expression of the Smad target gene ID1 and the tendon specific transcription factor scleraxis. The study shows that tenocyte-like cells undergo primarily Smad8 and p38 signalling after BMP-7 stimulation. The up-regulation of tendon related marker genes and matrix proteins such as Smad8/9, scleraxis and collagen I might lead to positive effects of BMP-7 treatment for rotator cuff repair, without significant induction of osteogenic and chondrogenic markers.
Comprehensive design of omnidirectional high-performance perovskite solar cells
Authors: Zhang Yutao , Xuan Yimin
Published: July 2016

The comprehensive design approach is established with coupled optical-electrical simulation for perovskite-based solar cell, which emerged as one of the most promising competitors to silicon solar cell for its low-cost fabrication and high PCE. The selection of structured surface, effect of geometry parameters, incident angle-dependence and polarization-sensitivity are considered in the simulation. The optical modeling is performed via the finite-difference time-domain method whilst the electrical properties are obtained by solving the coupled nonlinear equations of Poisson, continuity and drift-diffusion equations. The optical and electrical performances of five different structured surfaces are compared to select a best structured surface for perovskite solar cell. The effects of the geometry parameters on the optical and electrical properties of the perovskite cell are analyzed. The results indicate that the light harvesting is obviously enhanced by the structured surface. The electrical performance can be remarkably improved due to the enhanced light harvesting of the designed best structured surface. The angle-dependence for s- and p-polarizations is investigated. The structured surface exhibits omnidirectional behavior and favorable polarization-insensitive feature within a wide incident angle range. Such a comprehensive design approach can highlight the potential of perovskite cell for power conversion in the full daylight.
Parametric instability of optical non-Hermitian systems near the exceptional point
Authors: Zyablovsky A. A. , Andrianov E. S. , Pukhov A. A.
Published: July 2016

In contrast to Hermitian systems, the modes of non-Hermitian systems are generally nonorthogonal. As a result, the power of the system signal depends not only on the mode amplitudes but also on the phase shift between them. In this work, we show that it is possible to increase the mode amplitudes without increasing the power of the signal. Moreover, we demonstrate that when the system is at the exceptional point, any infinitesimally small change in the system parameters increases the mode amplitudes. As a result, the system becomes unstable with respect to such perturbation. We show such instability by using the example of two coupled waveguides in which loss prevails over gain and all modes are decaying. This phenomenon enables compensation for losses in dissipative systems and opens a wide range of applications in optics, plasmonics and optoelectronics, in which loss is an inevitable problem and plays a crucial role.
Receptor tyrosine kinase EphA7 is required for interneuron connectivity at specific subcellular compartments of granule cells
Authors: Beuter Simone , Ardi Ziv , Horovitz Omer , Wuchter Jennifer , Keller Stefanie , Saha Rinki , Tripathi Kuldeep , Anunu Rachel , Kehat Orli , Kriebel Martin , Richter-Levin Gal , Volkmer Hansjürgen
Published: July 2016

Neuronal transmission is regulated by the local circuitry which is composed of principal neurons targeted at different subcellular compartments by a variety of interneurons. However, mechanisms that contribute to the subcellular localisation and maintenance of GABAergic interneuron terminals are poorly understood. Stabilization of GABAergic synapses depends on clustering of the postsynaptic scaffolding protein gephyrin and its interaction with the guanine nucleotide exchange factor collybistin. Lentiviral knockdown experiments in adult rats indicated that the receptor tyrosine kinase EphA7 is required for the stabilisation of basket cell terminals on proximal dendritic and somatic compartments of granular cells of the dentate gyrus. EphA7 deficiency and concomitant destabilisation of GABAergic synapses correlated with impaired long-term potentiation and reduced hippocampal learning. Reduced GABAergic innervation may be explained by an impact of EphA7 on gephyrin clustering. Overexpression or ephrin stimulation of EphA7 induced gephyrin clustering dependent on the mechanistic target of rapamycin (mTOR) which is an interaction partner of gephyrin. Gephyrin interactions with mTOR become released after mTOR activation while enhanced interaction with the guanine nucleotide exchange factor collybistin was observed in parallel. In conclusion, EphA7 regulates gephyrin clustering and the maintenance of inhibitory synaptic connectivity via mTOR signalling.
Radicalization and Radical Catalysis of Biomass Sugars: Insights from First-principles Studies
Authors: Yang Gang , Zhu Chang , Zou Xianli , Zhou Lijun
Published: July 2016

Ab initio and density functional calculations are conducted to investigate the radicalization processes and radical catalysis of biomass sugars. Structural alterations due to radicalization generally focus on the radicalized sites and radicalization affects H-bonds in D-fructofuranose more than in D-glucopyranose, potentially with outcome of new H-bonds. Performances of different functionals and basis sets are evaluated for all radicalization processes and enthalpy changes and Gibbs free energies for these processes are presented with high accuracy, which can be referenced for subsequent experimental and theoretical studies. It shows that radicalization can be utilized for direct transformation of biomass sugars and for each sugar, C rather than O sites are always preferred for radicalization, thus suggesting the possibility to activate C-H bonds of biomass sugars. Radical catalysis is further combined with Brønsted acids and it clearly states that functionalization fundamentally regulates the catalytic effects of biomass sugars. In presence of explicit water molecules, functionalization significantly affects the activation barriers and reaction energies of protonation rather than dehydration steps. Tertiary butyl and phenyl groups with large steric hindrances or hydroxyl and amino groups resulting in high stabilities for protonation products drive the protonation steps to occur facilely at ambient conditions.
Benzothiazinethione is a potent preclinical candidate for the treatment of drug-resistant tuberculosis
Authors: Gao Chao , Peng Cuiting , Shi Yaojie , You Xinyu , Ran Kai , Xiong Lu , Ye Ting-hong , Zhang Lidan , Wang Ningyu , Zhu Yongxia , Liu Kun , Zuo Weiqiong , Yu Luoting , Wei Yuquan
Published: July 2016

New chemotherapeutic compounds are needed to combat multidrug-resistant Mycobacterium tuberculosis (Mtb), which remains a serious public-health challenge. Decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1 enzyme) has been characterized as an attractive therapeutic target to address this urgent demand. Herein, we have identified a new class of DprE1 inhibitors benzothiazinethiones as antitubercular agents. Benzothiazinethione analogue SKLB-TB1001 exhibited excellent activity against Mtb in the Microplate Alamar blue assay and intracellular model, meanwhile SKLB-TB1001 was also highly potent against multi-drug resistant extensively and drug resistant clinical isolates. Importantly, no antagonism interaction was found with any two-drug combinations tested in the present study and the combination of SKLB-TB1001 with rifampicin (RMP) was proved to be synergistic. Furthermore, benzothiazinethione showed superb in vivo antitubercular efficacy in an acute Mtb infection mouse model, significantly better than that of BTZ043. These data combined with the bioavailability and safety profiles of benzothiazinethione indicates SKLB-TB1001 is a promising preclinical candidate for the treatment of drug-resistant tuberculosis.
Molecular diagnosis of pediatric patients with citrin deficiency in China: SLC25A13 mutation spectrum and the geographic distribution
Authors: Lin Wei-Xia , Zeng Han-Shi , Zhang Zhan-Hui , Mao Man , Zheng Qi-Qi , Zhao Shu-Tao , Cheng Ying , Chen Feng-Ping , Wen Wang-Rong , Song Yuan-Zong
Published: July 2016

Citrin deficiency (CD) is a Mendelian disease due to biallelic mutations of SLC25A13 gene. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is the major pediatric CD phenotype, and its definite diagnosis relies on SLC25A13 genetic analysis. China is a vast country with a huge population, but the SLC25A13 genotypic features of CD patients in our country remains far from being well clarified. Via sophisticated molecular analysis, this study diagnosed 154 new CD patients in mainland China and identified 9 novel deleterious SLC25A13 mutations, i.e. c.103A > G, [c.329 − 154_c.468 + 2352del2646; c.468 + 2392_c.468 + 2393ins23], c.493C > T, c.755 − 1G > C, c.845_c.848 + 1delG, c.933_c.933 + 1insGCAG, c.1381G > T, c.1452 + 1G > A and c.1706_1707delTA. Among the 274 CD patients diagnosed by our group thus far, 41 SLC25A13 mutations/variations were detected. The 7 mutations c.775C > T, c.851_854del4, c.1078C > T, IVS11 + 1G > A, c.1364G > T, c.1399C > T and IVS16ins3kb demonstrated significantly different geographic distribution. Among the total 53 identified genotypes, only c.851_854del4/c.851_854del4 and c.851_854del4/c.1399C > T presented different geographic distribution. The northern population had a higher level of SLC25A13 allelic heterogeneity than those in the south. These findings enriched the SLC25A13 mutation spectrum and brought new insights into the geographic distribution of the variations and genotypes, providing reliable evidences for NICCD definite diagnosis and for the determination of relevant molecular targets in different Chinese areas.