Inspiration from heart development: Biomimetic development of functional human cardiac organoids

Publication date: October 2017
Source:Biomaterials, Volume 142
Author(s): Dylan J. Richards, Robert C. Coyle, Yu Tan, Jia Jia, Kerri Wong, Katelynn Toomer, Donald R. Menick, Ying Mei
Recent progress in human organoids has provided 3D tissue systems to model human development, diseases, as well as develop cell delivery systems for regenerative therapies. While direct differentiation of human embryoid bodies holds great promise for cardiac organoid production, intramyocardial cell organization during heart development provides biological foundation to fabricate human cardiac organoids with defined cell types. Inspired by the intramyocardial organization events in coronary vasculogenesis, where a diverse, yet defined, mixture of cardiac cell types self-organizes into functional myocardium in the absence of blood flow, we have developed a defined method to produce scaffold-free human cardiac organoids that structurally and functionally resembled the lumenized vascular network in the developing myocardium, supported hiPSC-CM development and possessed fundamental cardiac tissue-level functions. In particular, this development-driven strategy offers a robust, tunable system to examine the contributions of individual cell types, matrix materials and additional factors for developmental insight, biomimetic matrix composition to advance biomaterial design, tissue/organ-level drug screening, and cell therapy for heart repair.



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Recovery from Bell Palsy after Transplantation of Peripheral Blood Mononuclear Cells and Platelet-Rich Plasma

Summary: Peripheral blood mononuclear cells (PBMCs) are multipotent, and plasma contains growth factors involving tissue regeneration. We hypothesized that transplantation of PBMC-plasma will promote the recovery of paralyzed facial muscles in Bell palsy. This case report describes the effects of PBMC-plasma transplantations in a 27-year-old female patient with right side Bell palsy. On the affected side of the face, the treatment resulted in both morphological and functional recovery including voluntary facial movements. These findings suggest that PBMC-plasma has the capacity of facial muscle regeneration and provides a promising treatment strategy for patients suffering from Bell palsy or other neuromuscular disorders.

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Reconstruction of Severely Crushed Fingertip Amputations with Basic Fibroblast Growth Factor Slow Release System

No abstract available

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A unusual pediatric case of focal nodular hyperplasia studied with 99mTc-mebrofenin

Publication date: Available online 18 July 2017
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): Mª.V. Guiote Moreno, L.Mª. Mena Bares, A.M. Santos Bueno, E. Rodríguez Cáceres, J.A. Vallejo Casas




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Can metabolic tumour parameters on primary staging 18F-FDG-PET/CT contribute to risk stratification of primary central nervous system lymphomas for patient management as a prognostic model?

Publication date: Available online 18 July 2017
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): K. Okuyucu, E. Alagoz, S. Ince, S. Ozaydin, N. Arslan
ObjectivePrimary central nervous system (CNS) lymphoma is an aggressive and fatal extranodal non-Hodgkin lymphoma (NHL) jailed in CNS at initial diagnosis. Its prognosis is poor and the disease has a fatal outcome when compared with systemic NHL. A few baseline risk stratification scoring systems have been suggested to estimate the prognosis mainly based on serum lactate dehydrogenase (LDH) level, age, Karnofsky performance score (KPS), involvement of deep brain structures (DBS) and cerebrospinal fluid protein concentration. ¹⁸F-FDG-PET/CT has a high prognostic value with respect to overall survival (OS) and disease-free survival (DFS) in many cancers and lymphomas. We aimed to investigate metabolic tumour indexes on primary staging ¹⁸F-FDG-PET/CT as prognostic markers in primary CNS lymphoma.Material and methods14 patients with primary CNS diffuse large B-cell lymphoma (stage I) were enrolled in this retrospective cohort study. Primary staging ¹⁸F-FDG-PET/CT was performed and quantitative parameters like maximum standardized uptake value (SUVmax), average standardized uptake value (SUVmean), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were calculated for all patients before the treatment. Cox regression models were performed to determine their relation with survival time.ResultsIn the evaluation of all potential risk factors impacting recurrence/metastases (age, sex, serum LDH, involvement of DBS, SUVmax, SUVmean, MTV, TLG) with univariate analysis, TLG remained statistically significant (p=0.02).ConclusionMetabolic tumour parameters are useful in prognosis estimation of primary CNS lymphomas, especially TLG, which is the most important one and may play a role in patient management.



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Assessment of bone repair in critical-size defect in the calvarium of rats after the implantation of tricalcium phosphate beta (β-TCP)

Publication date: Available online 18 July 2017
Source:Acta Histochemica
Author(s): Leonardo de Freitas Silva, Erik Neiva Ribeiro de Carvalho Reis, Tânia Aparecida Barbara, João Paulo Bonardi, Idelmo Rangel Garcia, Paulo Sérgio Perri de Carvalho, Daniela Ponzoni
ObjectivesEvaluating the osteoconductive property of tricalcium phosphate beta (β-TCP) in comparison to that of inorganic bovine bone for repair in a critical-size defect in the rat calvarium.Materials andMethodsCritical-size defects of 7mm were made with a trephine in the calvaria of 48 Wistar rats. The animals were divided into four groups, and the defects in each group were filled with tricalcium phosphate beta (β-TCP), inorganic bovine bone (Bio-Oss), autogenous bone, or left empty. The animals were euthanized at two different time points (30 and 60days post-operation). All defects were recovered with a absorbable membrane of bovine cortical bone. Histological, histometric, and immunohistochemical (osteocalcin) assessments were carried out at 30 and 60days post-operation.ResultsAt 30days post-operation, all groups showed areas of bone formation, predominantly when autogenous grafts were used. However, there were no statistically significant differences between the treatment groups (p>0.05). After 60days, there were similarities in the bone formation patterns between the β-TCP (26.32±) and Bio-Oss (17.35±) groups (p=0.549). In terms of the immunohistochemical assessment of osteocalcin, the clot group showed light to moderate staining at 30 and 60days. The autogenous group showed moderate staining at 30days and moderate to intense staining after 60days. The Bio-Oss group showed light to moderate staining after 30days and intense staining at 60days. The β-TCP group showed moderate staining at 30 and 60days post-operation.Conclusionβ-TCP is a good osteoconductive material with similar effects to those of inorganic bovine bone graft and is suitable for utilization in the repair of bone defects.



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Dendritic Cell Lineage Potential in Human Early Hematopoietic Progenitors

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Julie Helft, Fernando Anjos-Afonso, Annemarthe G. van der Veen, Probir Chakravarty, Dominique Bonnet, Caetano Reis e Sousa
Conventional dendritic cells (cDCs) are thought to descend from a DC precursor downstream of the common myeloid progenitor (CMP). However, a mouse lymphoid-primed multipotent progenitor has been shown to generate cDCs following a DC-specific developmental pathway independent of monocyte and granulocyte poiesis. Similarly, here we show that, in humans, a large fraction of multipotent lymphoid early progenitors (MLPs) gives rise to cDCs, in particular the subset known as cDC1, identified by co-expression of DNGR-1 (CLEC9A) and CD141 (BDCA-3). Single-cell analysis indicates that over one-third of MLPs have the potential to efficiently generate cDCs. cDC1s generated from CMPs or MLPs do not exhibit differences in transcriptome or phenotype. These results demonstrate an early imprinting of the cDC lineage in human hematopoiesis and highlight the plasticity of developmental pathways giving rise to human DCs.

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Dendritic cells (DCs) are thought to descend from a DC precursor downstream of the common myeloid progenitor (CMP). Helft et al. show that multipotent lymphoid progenitors (MLPs) in humans are more efficient producers of CD141⁺DNGR-1⁺ cDC1s than CMPs. Therefore, DC lineage imprinting can occur in early hematopoietic progenitors in humans.


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KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Cemil Kerimoglu, M. Sadman Sakib, Gaurav Jain, Eva Benito, Susanne Burkhardt, Vincenzo Capece, Lalit Kaurani, Rashi Halder, Roberto Carlos Agís-Balboa, Roman Stilling, Hendrik Urbanke, Andrea Kranz, A. Francis Stewart, Andre Fischer
Kmt2a and Kmt2b are H3K4 methyltransferases of the Set1/Trithorax class. We have recently shown the importance of Kmt2b for learning and memory. Here, we report that Kmt2a is also important in memory formation. We compare the decrease in H3K4 methylation and de-regulation of gene expression in hippocampal neurons of mice with knockdown of either Kmt2a or Kmt2b. Kmt2a and Kmt2b control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity. Finally, we show that the decrease in H3K4 methylation resulting from Kmt2a knockdown partially recapitulates the pattern previously reported in CK-p25 mice, a model for neurodegeneration and memory impairment. Our findings point to the distinct functions of even closely related histone-modifying enzymes and provide essential insight for the development of more efficient and specific epigenetic therapies against brain diseases.

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Kerimoglu et al. report that the related histone methyltransferases Kmt2a and Kmt2b are both required for memory function but control different neuronal gene-expression programs. Loss of Kmt2a partially recapitulates changes in H3K4me3 seen in Alzheimer's models.


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CRKL Mediates p110β-Dependent PI3K Signaling in PTEN-Deficient Cancer Cells

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Jing Zhang, Xueliang Gao, Fabienne Schmit, Guillaume Adelmant, Michael J. Eck, Jarrod A. Marto, Jean J. Zhao, Thomas M. Roberts
The p110β isoform of PI3K is preferentially activated in many tumors deficient in the phosphatase and tensin homolog (PTEN). However, the mechanism(s) linking PTEN loss to p110β activation remain(s) mysterious. Here, we identify CRKL as a member of the class of PI3Kβ-interacting proteins. Silencing CRKL expression in PTEN-null human cancer cells leads to a decrease in p110β-dependent PI3K signaling and cell proliferation. In contrast, CRKL depletion does not impair p110α-mediated signaling. Further study showed that CRKL binds to tyrosine-phosphorylated p130Cas in PTEN-null cancer cells. Since Src family kinases are known both to be regulated by PTEN and to phosphorylate and activate p130Cas, we tested and found that Src inhibition cooperated with p110β inhibition to suppress the growth of PTEN-null cells. These data suggest both a potential mechanism linking PTEN loss to p110β activation and the possible benefit of dual inhibition of Src and PI3K for PTEN-null tumors.

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Zhang et al. find a role for CRKL in regulating p110β-dependent PI3K activity in PTEN-null cancer cells through its association with p110β/p85. A PTEN/FAK/Src/p130Cas axis may activate CRKL/p110β in PTEN-null cancer cells. Src inhibition cooperates with PI3K or p110β inhibition to suppress the growth of PTEN-null tumor cells.


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Crosstalk between Regulatory T Cells and Tumor-Associated Dendritic Cells Negates Anti-tumor Immunity in Pancreatic Cancer

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Jung-Eun Jang, Cristina H. Hajdu, Caroline Liot, George Miller, Michael L. Dustin, Dafna Bar-Sagi
Regulatory T (Treg) cell infiltration constitutes a prominent feature of pancreatic ductal adenocarcinoma (PDA). However, the immunomodulatory function of Treg cells in PDA is poorly understood. Here, we demonstrate that Treg cell ablation is sufficient to evoke effective anti-tumor immune response in early and advanced pancreatic tumorigenesis in mice. This response is dependent on interferon-γ (IFN-γ)-producing cytotoxic CD8⁺ T cells. We show that Treg cells engage in extended interactions with tumor-associated CD11c⁺ dendritic cells (DCs) and restrain their immunogenic function by suppressing the expression of costimulatory ligands necessary for CD8⁺ T cell activation. Consequently, tumor-associated CD8⁺ T cells fail to display effector activities when Treg cell ablation is combined with DC depletion. We propose that tumor-infiltrating Treg cells can promote immune tolerance by suppressing tumor-associated DC immunogenicity. The therapeutic manipulation of this axis might provide an effective approach for the targeting of PDA.

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Pancreatic tumors recruit dendritic cells that can switch between preventing or promoting immune responses. Jang et al. show that regulatory T cells are responsible for instructing the dendritic cells to prevent anti-tumor immunity. Removing the regulatory T cell subset allows dendritic cells to induce a potent anti-tumor immune response.


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Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Ashwin Unnikrishnan, Elli Papaemmanuil, Dominik Beck, Nandan P. Deshpande, Arjun Verma, Ashu Kumari, Petter S. Woll, Laura A. Richards, Kathy Knezevic, Vashe Chandrakanthan, Julie A.I. Thoms, Melinda L. Tursky, Yizhou Huang, Zara Ali, Jake Olivier, Sally Galbraith, Austin G. Kulasekararaj, Magnus Tobiasson, Mohsen Karimi, Andrea Pellagatti, Susan R. Wilson, Robert Lindeman, Boris Young, Raj Ramakrishna, Christopher Arthur, Richard Stark, Philip Crispin, Jennifer Curnow, Pauline Warburton, Fernando Roncolato, Jacqueline Boultwood, Kevin Lynch, Sten Eirik W. Jacobsen, Ghulam J. Mufti, Eva Hellstrom-Lindberg, Marc R. Wilkins, Karen L. MacKenzie, Jason W.H. Wong, Peter J. Campbell, John E. Pimanda
Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5-azacytidine (AZA) is the most effective pharmacological option, but only ∼50% of patients respond. A response only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs) in the cell cycle. Non-responder HPC quiescence is mediated by integrin α5 (ITGA5) signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders.

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Unnikrishnan et al. discover that patients who fail to respond to frontline therapy with 5-azacitidine (AZA) have a higher baseline proportion of quiescent hematopoietic progenitor cells. Longitudinal sampling reveals that, although AZA response fails to eradicate clonal hematopoiesis, it restores functional hematopoiesis from progenitors with a lower mutational burden.


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Crystal Structure of the Human Ribosome in Complex with DENR-MCT-1

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Ivan B. Lomakin, Elena A. Stolboushkina, Anand T. Vaidya, Chenguang Zhao, Maria B. Garber, Sergey E. Dmitriev, Thomas A. Steitz
The repertoire of the density-regulated protein (DENR) and the malignant T cell-amplified sequence 1 (MCT-1/MCTS1) oncoprotein was recently expanded to include translational control of a specific set of cancer-related mRNAs. DENR and MCT-1 form the heterodimer, which binds to the ribosome and operates at both translation initiation and reinitiation steps, though by a mechanism that is yet unclear. Here, we determined the crystal structure of the human small ribosomal subunit in complex with DENR-MCT-1. The structure reveals the location of the DENR-MCT-1 dimer bound to the small ribosomal subunit. The binding site of the C-terminal domain of DENR on the ribosome has a striking similarity with those of canonical initiation factor 1 (eIF1), which controls the fidelity of translation initiation and scanning. Our findings elucidate how the DENR-MCT-1 dimer interacts with the ribosome and have functional implications for the mechanism of unconventional translation initiation and reinitiation.

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Some HCV-like viruses and specific cellular mRNAs use the DENR-MCT-1 heterodimer to initiate protein synthesis by an unknown mechanism. Lomakin et al. determined by X-ray crystallography the binding interface between the human small ribosomal subunit and the DENR-MCT-1 heterodimer, which is important for the DENR-MCT-1 function in non-canonical translation initiation and reinitiation.


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A Positive Feedback Loop between Sestrin2 and mTORC2 Is Required for the Survival of Glutamine-Depleted Lung Cancer Cells

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Jun-Kyu Byun, Yeon-Kyung Choi, Ji-Hyun Kim, Ji Yun Jeong, Hui-Jeon Jeon, Mi-Kyung Kim, Ilseon Hwang, Shin-Yup Lee, You Mie Lee, In-Kyu Lee, Keun-Gyu Park
Proper regulation of mTORC1 and mTORC2 upon nutrient starvation is critical for cancer cell survival. Upregulation of Sestrin2 in response to glutamine deprivation rescues cell death by suppressing mTORC1. However, the contribution of mTORC2 to Sestrin2-mediated mTORC1 suppression remains unclear. Here, we report that both Sestrin2 and mTORC2 are upregulated in glutamine-depleted lung cancer cells. Moreover, glutamine depletion caused Sestrin2 to associate with mTORC2, which was required for the increase in Sestrin2 protein stability and the reduction in mTORC1 activity. Ultimately, differential regulation of mTORC1 and 2 by Sestrin2 reprogramed lipid metabolism and enabled glutamine-depleted lung cancer cells to survive by maintaining energy and redox balance. Importantly, combined inhibition of glutamine utilization and Sestrin2 induced lung cancer cell death both in vitro and in vivo. This study shows that differential Sestrin2-mediated regulation of mTORC1 and mTORC2 is necessary for the survival of glutamine-depleted lung cancer cells.

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Byun et al. find that a positive feedback loop between Sestrin2 and mTORC2 is necessary to suppress mTORC1 activity in glutamine-depleted lung cancer cells. Differential regulation of mTORC1 and mTORC2 by Sestrin2 prevents ATP depletion and maintains redox balance, enabling lung cancer cells to survive under glutamine-depleted conditions.


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The Lysine Acetyltransferase GCN5 Is Required for iNKT Cell Development through EGR2 Acetylation

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Yajun Wang, Chawon Yun, Beixue Gao, Yuanming Xu, Yana Zhang, Yiming Wang, Qingfei Kong, Fang Zhao, Chyung-Ru Wang, Sharon Y.R. Dent, Jian Wang, Xiangping Xu, Hua-Bin Li, Deyu Fang
The development of CD1d-restricted invariant natural killer T (iNKT) cells, a population that is critical for both innate and adaptive immunity, is regulated by multiple transcription factors, but the molecular mechanisms underlying how the transcriptional activation of these factors are regulated during iNKT development remain largely unknown. We found that the histone acetyltransferase general control non-derepressible 5 (GCN5) is essential for iNKT cell development during the maturation stage. GCN5 deficiency blocked iNKT cell development in a cell-intrinsic manner. At the molecular level, GCN5 is a specific lysine acetyltransferase of early growth responsive gene 2 (EGR2), a transcription factor required for iNKT cell development. GCN5-mediated acetylation positively regulated EGR2 transcriptional activity, and both genetic and pharmacological GCN5 suppression specifically inhibited the transcription of EGR2 target genes in iNKT cells, including Runx1, promyelocytic leukemia zinc finger protein (PLZF), interleukin (IL)-2Rb, and T-bet. Therefore, our study revealed GCN5-mediated EGR2 acetylation as a molecular mechanism that regulates iNKT development.

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Wang et al. demonstrate that GCN5 is essential for programing iNKT cell development. Loss of GCN5 blocks iNKT cell development in a cell-intrinsic manner. GCN5 directly catalyzes the iNKT lineage-specific factor EGR2 to turn on its transcriptional activity for the expression of genes required for iNKT development.


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The Transcription Factor Tcf1 Contributes to Normal NK Cell Development and Function by Limiting the Expression of Granzymes

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Beena Jeevan-Raj, Jasmine Gehrig, Mélanie Charmoy, Vijaykumar Chennupati, Camille Grandclément, Paolo Angelino, Mauro Delorenzi, Werner Held
The transcription factor Tcf1 is essential for the development of natural killer (NK) cells. However, its precise role has not been clarified. Our combined analysis of Tcf1-deficient and transgenic mice indicated that Tcf1 guides NK cells through three stages of development. Tcf1 expression directed bone marrow progenitors toward the NK cell lineage and ensured the survival of NK-committed cells, and its downregulation was needed for terminal maturation. Impaired survival of NK-committed cells was due to excessive expression of granzyme B (GzmB) and other granzyme family members, which induced NK cell self-destruction during maturation and following activation with cytokines or target cells. Mechanistically, Tcf1 binding reduced the activity of a Gzmb-associated regulatory element, and this accounted for the reduced Gzmb expression in Tcf1-expressing NK cells. These data identify an unexpected requirement to limit the expression of cytotoxic effector molecules for the normal expansion and function of NK cells.

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The transcription factor Tcf1 is essential for NK cell development, but its role has not been clarified. Jeevan-Raj et al. identify a stage-specific role for Tcf1 in ensuring the survival of NK-committed cells. Tcf1 limited the expression of granzymes, thereby preventing granzyme-mediated NK cell self-destruction.


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Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Christopher M. Webster, Elizabeth C. Pino, Christopher E. Carr, Lianfeng Wu, Ben Zhou, Lucydalila Cedillo, Michael C. Kacergis, Sean P. Curran, Alexander A. Soukas
Organisms must execute metabolic defenses to survive nutrient deprivation. We performed a genome-wide RNAi screen in Caenorhabditis elegans to identify fat regulatory genes indispensable for starvation resistance. Here, we show that opposing proteostasis pathways are principal determinants of starvation survival. Reduced function of cytoplasmic aminoacyl tRNA synthetases (ARS genes) increases fat mass and extends starvation survival, whereas reduced proteasomal function reduces fat and starvation survival. These opposing pathways converge on AMP-activated protein kinase (AMPK) as the critical effector of starvation defenses. Extended starvation survival in ARS deficiency is dependent upon increased proteasome-mediated activation of AMPK. When the proteasome is inhibited, neither starvation nor ARS deficiency can fully activate AMPK, leading to greatly diminished starvation survival. Thus, activity of the proteasome and AMPK are mechanistically linked and highly correlated with starvation resistance. Conversely, aberrant activation of the proteostasis-AMPK axis during nutritional excess may have implications for obesity and cardiometabolic diseases.

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Using a genome-wide screen for fat regulatory genes in C. elegans, Webster et al. define a proteostasis-AMPK signaling axis that is central to organismal starvation defenses. The results suggest that enhanced survival under elevated proteasome activity is due to AMPK activation and not to increased fuel availability.


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Cold-Inducible SIRT6 Regulates Thermogenesis of Brown and Beige Fat

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Lu Yao, Xiaona Cui, Qi Chen, Xiaoying Yang, Fude Fang, Jun Zhang, Guoqing Liu, Wanzhu Jin, Yongsheng Chang
Promoting development and function of brown and beige fat may reduce obesity. Here, we show that fat SIRT6 expression is markedly induced by cold exposure and a β-adrenergic agonist. Deletion of SIRT6 in adipose tissue impairs the thermogenic function of brown adipocytes, causing a morphological "whitening" of brown fat, reduced oxygen (O2) consumption, obesity, decreased core body temperature, and cold sensitivity. Fat SIRT6-deleted mice exhibit increased blood glucose levels, severe insulin resistance, and hepatic steatosis. Moreover, SIRT6 deficiency inhibits the browning of white adipose tissue (WAT) following cold exposure or β3-agonist treatment. Depletion of SIRT6 expression in brown adipocytes reduces expression of thermogenic genes, causing a reduction in cellular respiration. Conversely, SIRT6 overexpression in primary fat cells stimulates the thermogenic program. Mechanistically, SIRT6 interacts with and promotes phospho-ATF2 binding to the PGC-1α gene promoter to activate its expression. The present study reveals a critical role for SIRT6 in regulating thermogenesis of fat.

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Enhancing thermogenesis in brown and beige fat represents a potential treatment for obesity. Yao et al. demonstrate that SIRT6 is essential for thermogenesis of brown and beige fat. SIRT6 deficiency in adipose tissue predisposes mice to obesity and related metabolic diseases.


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Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Jieun Lee, Joseph Choi, Ebru S. Selen Alpergin, Liang Zhao, Thomas Hartung, Susanna Scafidi, Ryan C. Riddle, Michael J. Wolfgang
The liver has a large capacity for mitochondrial fatty acid β-oxidation, which is critical for systemic metabolic adaptations such as gluconeogenesis and ketogenesis. To understand the role of hepatic fatty acid oxidation in response to a chronic high-fat diet (HFD), we generated mice with a liver-specific deficiency of mitochondrial long-chain fatty acid β-oxidation (Cpt2^L−/− mice). Paradoxically, Cpt2^L−/− mice were resistant to HFD-induced obesity and glucose intolerance with an absence of liver damage, although they exhibited serum dyslipidemia, hepatic oxidative stress, and systemic carnitine deficiency. Feeding an HFD induced hepatokines in mice, with a loss of hepatic fatty acid oxidation that enhanced systemic energy expenditure and suppressed adiposity. Additionally, the suppression in hepatic gluconeogenesis was sufficient to improve HFD-induced glucose intolerance. These data show that inhibiting hepatic fatty acid oxidation results in a systemic hormetic response that protects mice from HFD-induced obesity and glucose intolerance.

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Lee et al. show that, contrary to expectations, the loss of hepatic fatty acid oxidation (FAO) confers resistance to weight gain and adiposity in response to a high-fat diet. Additionally, they show that loss of hepatic FAO—and, consequently, hepatic gluconeogenesis—protects mice from high-fat-diet-induced glucose intolerance.


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XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Kate E. Lawlor, Rebecca Feltham, Monica Yabal, Stephanie A. Conos, Kaiwen W. Chen, Stephanie Ziehe, Carina Graß, Yifan Zhan, Tan A. Nguyen, Cathrine Hall, Angelina J. Vince, Simon M. Chatfield, Damian B. D'Silva, Kenneth C. Pang, Kate Schroder, John Silke, David L. Vaux, Philipp J. Jost, James E. Vince
X-linked Inhibitor of Apoptosis (XIAP) deficiency predisposes people to pathogen-associated hyperinflammation. Upon XIAP loss, Toll-like receptor (TLR) ligation triggers RIPK3-caspase-8-mediated IL-1β activation and death in myeloid cells. How XIAP suppresses these events remains unclear. Here, we show that TLR-MyD88 causes the proteasomal degradation of the related IAP, cIAP1, and its adaptor, TRAF2, by inducing TNF and TNF Receptor 2 (TNFR2) signaling. Genetically, we define that myeloid-specific cIAP1 loss promotes TLR-induced RIPK3-caspase-8 and IL-1β activity in the absence of XIAP. Importantly, deletion of TNFR2 in XIAP-deficient cells limited TLR-MyD88-induced cIAP1-TRAF2 degradation, cell death, and IL-1β activation. In contrast to TLR-MyD88, TLR-TRIF-induced interferon (IFN)β inhibited cIAP1 loss and consequent cell death. These data reveal how, upon XIAP deficiency, a TLR-TNF-TNFR2 axis drives cIAP1-TRAF2 degradation to allow TLR or TNFR1 activation of RIPK3-caspase-8 and IL-1β. This mechanism may explain why XIAP-deficient patients can exhibit symptoms reminiscent of patients with activating inflammasome mutations.

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Lawlor et al. find that TLR signaling induces TNF and TNFR2 to trigger degradation of the IAP family member cIAP1. In the absence of XIAP, these events induce TLR-RIPK3-caspase-8-driven NLRP3 and IL-1β activation and cell death.


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Dynamic Control of Dendritic mRNA Expression by CNOT7 Regulates Synaptic Efficacy and Higher Cognitive Function

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Rhonda L. McFleder, Fernanda Mansur, Joel D. Richter
Translation of mRNAs in dendrites mediates synaptic plasticity, the probable cellular basis of learning and memory. Coordination of translational inhibitory and stimulatory mechanisms, as well as dendritic transport of mRNA, is necessary to ensure proper control of this local translation. Here, we find that the deadenylase CNOT7 dynamically regulates dendritic mRNA translation and transport, as well as synaptic plasticity and higher cognitive function. In cultured hippocampal neurons, synaptic stimulation induces a rapid decrease in CNOT7, which, in the short-term, results in poly(A) tail lengthening of target mRNAs. However, at later times following stimulation, decreased poly(A) and dendritic localization of mRNA take place, similar to what is observed when CNOT7 is depleted over several days. In mice, CNOT7 is essential for hippocampal-dependent learning and memory. This study identifies CNOT7 as an important regulator of RNA transport and translation in dendrites, as well as higher cognitive function.

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McFleder et al. find that CNOT7, the major deadenylase in eukaryotes, has a specialized role in neurons. CNOT7 regulates the dendritic localization and translation of specific mRNAs and mediates synaptic plasticity and learning and memory in mice.


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Emi2 Is Essential for Mouse Spermatogenesis

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Lakshmi Gopinathan, Radoslaw Szmyd, Diana Low, M. Kasim Diril, Heng-Yu Chang, Vincenzo Coppola, Kui Liu, Lino Tessarollo, Ernesto Guccione, Ans M.M. van Pelt, Philipp Kaldis
The meiotic functions of Emi2, an inhibitor of the APC/C complex, have been best characterized in oocytes where it mediates metaphase II arrest as a component of the cytostatic factor. We generated knockout mice to determine the in vivo functions of Emi2—in particular, its functions in the testis, where Emi2 is expressed at high levels. Male and female Emi2 knockout mice are viable but sterile, indicating that Emi2 is essential for meiosis but dispensable for embryonic development and mitotic cell divisions. We found that, besides regulating cell-cycle arrest in mouse eggs, Emi2 is essential for meiosis I progression in spermatocytes. In the absence of Emi2, spermatocytes arrest in early diplotene of prophase I. This arrest is associated with decreased Cdk1 activity and was partially rescued by a knockin mouse model of elevated Cdk1 activity. Additionally, we detected expression of Emi2 in spermatids and sperm, suggesting potential post-meiotic functions for Emi2.

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Gopinathan et al. use mouse genetics to characterize the in vivo functions of Emi2, a meiotic inhibitor of APC/C. Emi2 knockout mice are sterile, revealing that Emi2 is essential for oocytes and spermatocytes to complete meiotic divisions. Impaired Cdk1 activity upon loss of Emi2 contributes to spermatogenic defects.


http://ift.tt/2uxBXQm

Robust Identification of Developmentally Active Endothelial Enhancers in Zebrafish Using FANS-Assisted ATAC-Seq

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Aurelie Quillien, Mary Abdalla, Jun Yu, Jianhong Ou, Lihua Julie Zhu, Nathan D. Lawson
Identification of tissue-specific and developmentally active enhancers provides insights into mechanisms that control gene expression during embryogenesis. However, robust detection of these regulatory elements remains challenging, especially in vertebrate genomes. Here, we apply fluorescent-activated nuclei sorting (FANS) followed by Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) to identify developmentally active endothelial enhancers in the zebrafish genome. ATAC-seq of nuclei from Tg(fli1a:egfp)^y1 transgenic embryos revealed expected patterns of nucleosomal positioning at transcriptional start sites throughout the genome and association with active histone modifications. Comparison of ATAC-seq from GFP-positive and -negative nuclei identified more than 5,000 open elements specific to endothelial cells. These elements flanked genes functionally important for vascular development and that displayed endothelial-specific gene expression. Importantly, a majority of tested elements drove endothelial gene expression in zebrafish embryos. Thus, FANS-assisted ATAC-seq using transgenic zebrafish embryos provides a robust approach for genome-wide identification of active tissue-specific enhancer elements.

Graphical abstract

Teaser

Quillien et al. apply ATAC-seq to nuclei isolated from transgenic zebrafish embryos to successfully identify a compendium of active endothelial-specific enhancer elements.


http://ift.tt/2uxU0G0

Proteomic and Metabolomic Characterization of a Mammalian Cellular Transition from Quiescence to Proliferation

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Ho-Joon Lee, Mark P. Jedrychowski, Arunachalam Vinayagam, Ning Wu, Ng Shyh-Chang, Yanhui Hu, Chua Min-Wen, Jodene K. Moore, John M. Asara, Costas A. Lyssiotis, Norbert Perrimon, Steven P. Gygi, Lewis C. Cantley, Marc W. Kirschner
There exist similarities and differences in metabolism and physiology between normal proliferative cells and tumor cells. Once a cell enters the cell cycle, metabolic machinery is engaged to facilitate various processes. The kinetics and regulation of these metabolic changes have not been properly evaluated. To correlate the orchestration of these processes with the cell cycle, we analyzed the transition from quiescence to proliferation of a non-malignant murine pro-B lymphocyte cell line in response to IL-3. Using multiplex mass-spectrometry-based proteomics, we show that the transition to proliferation shares features generally attributed to cancer cells: upregulation of glycolysis, lipid metabolism, amino-acid synthesis, and nucleotide synthesis and downregulation of oxidative phosphorylation and the urea cycle. Furthermore, metabolomic profiling of this transition reveals similarities to cancer-related metabolic pathways. In particular, we find that methionine is consumed at a higher rate than that of other essential amino acids, with a potential link to maintenance of the epigenome.

Graphical abstract

Teaser

Lee et al. generate and integrate quantitative time-course proteomic and metabolomic profiling data to find that global metabolic reprogramming of an IL-3 activation resembles metabolic rewiring in cancer with high consumption of methionine in G1.


http://ift.tt/2vhuTET

Proteomic Analysis of the Human Tankyrase Protein Interaction Network Reveals Its Role in Pexophagy

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Xu Li, Han Han, Mao-Tian Zhou, Bing Yang, Albert Paul Ta, Nan Li, Junjie Chen, Wenqi Wang
Tankyrase 1 (TNKS) and tankyrase 2 (TNKS2) belong to the poly(ADP-ribose) polymerase family of proteins, which use nicotinamide adenine dinucleotide to modify substrate proteins with ADP-ribose modifications. Emerging evidence has revealed the pathological relevance of TNKS and TNKS2, and identified these two enzymes as potential drug targets. However, the cellular functions and regulatory mechanisms of TNKS/2 are still largely unknown. Through a proteomic analysis, we defined the protein-protein interaction network for human TNKS/2 and revealed more than 100 high-confidence interacting proteins with numerous biological functions in this network. Finally, through functional validation, we uncovered a role for TNKS/2 in peroxisome homeostasis and determined that this function is independent of TNKS enzyme activities. Our proteomic study of the TNKS/2 protein interaction network provides a rich resource for further exploration of tankyrase functions in numerous cellular processes.

Graphical abstract

Teaser

Li at al. establish a protein-protein interaction network for human TNKS and TNKS2, two poly(ADP-ribose) polymerase family proteins. They examine and validate the peroxisomal localization of these tankyrases and link them to peroxisome homeostasis.


http://ift.tt/2vgK1Cx

CRISPR-Mediated Integration of Large Gene Cassettes Using AAV Donor Vectors

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Rasmus O. Bak, Matthew H. Porteus
The CRISPR/Cas9 system has recently been shown to facilitate high levels of precise genome editing using adeno-associated viral (AAV) vectors to serve as donor template DNA during homologous recombination (HR). However, the maximum AAV packaging capacity of ∼4.5 kb limits the donor size. Here, we overcome this constraint by showing that two co-transduced AAV vectors can serve as donors during consecutive HR events for the integration of large transgenes. Importantly, the method involves a single-step procedure applicable to primary cells with relevance to therapeutic genome editing. We use the methodology in primary human T cells and CD34⁺ hematopoietic stem and progenitor cells to site-specifically integrate an expression cassette that, as a single donor vector, would otherwise amount to a total of 6.5 kb. This approach now provides an efficient way to integrate large transgene cassettes into the genomes of primary human cells using HR-mediated genome editing with AAV vectors.

Graphical abstract

Teaser

Integration of transgenes into specific sites of the genome of primary cells using CRISPR/Cas9 and AAV donor vectors is currently hampered by the limited packaging capacity of AAV. Bak and Porteus now report a method for efficient integration of large transgenes that exceed the capacity of a single AAV.


http://ift.tt/2vh6YFL

An Atlas of Human Regulatory T Helper-like Cells Reveals Features of Th2-like Tregs that Support a Tumorigenic Environment

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Leena Halim, Marco Romano, Reuben McGregor, Isabel Correa, Polychronis Pavlidis, Nathali Grageda, Sec-Julie Hoong, Muhammed Yuksel, Wayel Jassem, Rosalind F. Hannen, Mark Ong, Olivia Mckinney, Bu'Hussain Hayee, Sophia N. Karagiannis, Nicholas Powell, Robert I. Lechler, Estefania Nova-Lamperti, Giovanna Lombardi
Regulatory T cells (Tregs) play a pivotal role in maintaining immunological tolerance, but they can also play a detrimental role by preventing antitumor responses. Here, we characterized T helper (Th)-like Treg subsets to further delineate their biological function and tissue distribution, focusing on their possible contribution to disease states. RNA sequencing and functional assays revealed that Th2-like Tregs displayed higher viability and autocrine interleukin-2 (IL-2)-mediated activation than other subsets. Th2-like Tregs were preferentially found in tissues rather than circulation and exhibited the highest migratory capacity toward chemokines enriched at tumor sites. These cellular responses led us to hypothesize that this subset could play a role in maintaining a tumorigenic environment. Concurrently, Th2-like Tregs were enriched specifically in malignant tissues from patients with melanoma and colorectal cancer compared to healthy tissue. Overall, our results suggest that Th2-like Tregs may contribute to a tumorigenic environment due to their increased cell survival, higher migratory capacity, and selective T-effector suppressive ability.

Graphical abstract

Teaser

Halim et al. provide a comprehensive transcriptomic and functional analysis of circulating Th-like Tregs, revealing unique features in Th2-like Tregs and a significant enrichment of this subset in patients with melanoma and colorectal cancer. This suggests that Th2-like Tregs play a major role in maintaining a tumorigenic environment.


http://ift.tt/2uHi6Pf

Erratum to: Petrol filling workers as biomonitor of PAH exposure and functional health capacity in resource-limited settings of city Rawalpindi, Pakistan

http://ift.tt/2tdAo69

Role of glutathione in the regulation of epigenetic mechanisms in disease

Publication date: November 2017
Source:Free Radical Biology and Medicine, Volume 112
Author(s): José Luis García-Giménez, Carlos Romá-Mateo, Gisselle Pérez-Machado, Lorena Peiró-Chova, Federico V. Pallardó
Epigenetics is a rapidly growing field that studies gene expression modifications not involving changes in the DNA sequence. Histone H3, one of the basic proteins in the nucleosomes that make up chromatin, is S-glutathionylated in mammalian cells and tissues, making Gamma-L-glutamyl-L-cysteinylglycine, glutathione (GSH), a physiological antioxidant and second messenger in cells, a new post-translational modifier of the histone code that alters the structure of the nucleosome. However, the role of GSH in the epigenetic mechanisms likely goes beyond a mere structural function. Evidence supports the hypothesis that there is a link between GSH metabolism and the control of epigenetic mechanisms at different levels (i.e., substrate availability, enzymatic activity for DNA methylation, changes in the expression of microRNAs, and participation in the histone code). However, little is known about the molecular pathways by which GSH can control epigenetic events. Studying mutations in enzymes involved in GSH metabolism and the alterations of the levels of cofactors affecting epigenetic mechanisms appears challenging. However, the number of diseases induced by aberrant epigenetic regulation is growing, so elucidating the intricate network between GSH metabolism, oxidative stress and epigenetics could shed light on how their deregulation contributes to the development of neurodegeneration, cancer, metabolic pathologies and many other types of diseases.

Graphical abstract

http://ift.tt/2tdQcG3

Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients

Publication date: Available online 18 July 2017
Source:Cancer Treatment Reviews
Author(s): Filip Janku
The phosphoinositide 3-kinase (PI3K) pathway is an intracellular signaling pathway that has regulatory roles in cell survival, proliferation, and differentiation, and a critical role in tumorigenesis. In cancer, multiple studies have investigated the therapeutic targeting of the PI3K pathway, and multiple inhibitors targeting PI3K and its isoforms, protein kinase B/AKT, mammalian target of rapamycin (mTOR), and other pathway proteins have been developed. For the treatment of solid tumors, only allosteric mTOR inhibitors, such as everolimus and temsirolimus, are currently approved for clinical use. This review describes the PI3K inhibitors that have progressed from the laboratory to late-stage clinical trials, and discusses the challenges that have prevented other compounds from doing the same. Challenges to the therapeutic effectiveness of some PI3K inhibitors include the absence of reliable and effective biomarkers, their limited efficacy as single agents, insufficient development of rational therapeutic combinations, the use of schedules with a variety of off-target effects, and suboptimal therapeutic exposures. Therefore, with regard to PI3K inhibitors currently in late-stage clinical trials, the identification of appropriate biomarkers of efficacy and the development of optimal combination regimens and dosing schedules are likely to be important for graduation into clinical practice.



http://ift.tt/2uxT6cz

Treatment of late sequelae after radiotherapy for head and neck cancer

Publication date: Available online 18 July 2017
Source:Cancer Treatment Reviews
Author(s): Primož Strojan, Katherine A. Hutcheson, Avraham Eisbruch, Jonathan J. Beitler, Johannes A. Langendijk, Anne W.M. Lee, June Corry, William M. Mendenhall, Robert Smee, Alessandra Rinaldo, Alfio Ferlito
Radiotherapy (RT) is used to treat approximately 80% of patients with cancer of the head and neck. Despite enormous advances in RT planning and delivery, a significant number of patients will experience radiation-associated toxicities, especially those treated with concurrent systemic agents. Many effective management options are available for acute RT-associated toxicities, but treatment options are much more limited and of variable benefit among patients who develop late sequelae after RT. The adverse impact of developing late tissue damage in irradiated patients may range from bothersome symptoms that negatively affect their quality of life to severe life-threatening complications. In the region of the head and neck, among the most problematic late effects are impaired function of the salivary glands and swallowing apparatus. Other tissues and structures in the region may be at risk, depending mainly on the location of the irradiated tumor relative to the mandible and hearing apparatus. Here, we review the available evidence on the use of different therapeutic strategies to alleviate common late sequelae of RT in head and neck cancer patients, with a focus on the critical assessment of the treatment options for xerostomia, dysphagia, mandibular osteoradionecrosis, trismus, and hearing loss.



http://ift.tt/2uyaxKe

Targets of ubiquitin like system in mycobacteria and related actinobacterial species

Publication date: Available online 18 July 2017
Source:Microbiological Research
Author(s): Yusuf Akhter, Shweta Thakur
Protein turnover and recycling is a prerequisite in all living organisms to maintain normal cellular physiology. Many bacteria are proteasome deficient but they possess typical protease enzymes for carrying out protein turnover. However, several groups of actinobacteria such as mycobacteria harbor both proteasome and proteases. In these bacteria, for cellular protein, turnover the target proteins undergo post-translational modification referred as pupylation in which a small protein Pup (prokaryotic ubiquitin-like protein) is tagged to the specific lysine residues of the target proteins and after that those target proteins undergo proteasomal degradation. Thus, Pup serves as a degradation signal, helps in directing proteins toward the bacterial proteasome for a turnover. Although the Pup–proteasome system has a multifaceted role in environmental stresses, pathogenicity, regulation of cellular signaling, but the fate of all types of pupylation such as mono and polypupylation on the proteins is still not completely understood. In this review, we present the mechanisms involved in the activation and conjugation of Pup to the target proteins, describing the structural sketch of pupylation and fundamental differences between the eukaryotic ubiquitin–proteasome and bacterial Pup–proteasome systems. We are also presenting the concise classification and cataloging of the complete battery of experimentally identified Pup-substrates from various species of actinobacteria.



http://ift.tt/2uHaJr6

Artificial Intelligence in Medicine AIME 2015

Publication date: Available online 18 July 2017
Source:Artificial Intelligence in Medicine
Author(s): John H. Holmes, Lucia Sacchi, Riccardo Bellazzi, Niels Peek




http://ift.tt/2toDatv

Employing decomposable partially observable Markov decision processes to control gene regulatory networks

Publication date: Available online 18 July 2017
Source:Artificial Intelligence in Medicine
Author(s): Utku Erdogdu, Faruk Polat, Reda Alhajj
ObjectiveFormulate the induction and control of gene regulatory networks (GRNs) from gene expression data using Partially Observable Markov Decision Processes (POMDPs).Methods and materialDifferent approaches exist to model GRNs; they are mostly simulated as mathematical models that represent relationships between genes. Actually, it has been realized that biological functions at the cellular level are controlled by genes; thus, by controlling the behavior of genes, it is possible to regulate these biological functions. The GRN control problem has been studied mostly with the aid of probabilistic Boolean networks, and corresponding control policies have been devised. Though turns into a more challenging problem, we argue that partial observability would be a more natural and realistic method for handling the control of GRNs. Partial observability is a fundamental aspect of the problem; it is mostly ignored and substituted by assumption that states of GRN are known precisely, prescribed as full observability. We propose a method for the construction of POMDP model of GRN from only raw gene expression data which is original and novel. Then, we introduce a novel approach to decompose/factor the POMDP model into sub-POMDP's in order to solve it efficiently with the help of divide-and-conquer strategy.ResultsIn order to demonstrate the effectiveness of the proposed solution we experimented with two synthetic network and one real network data from the literature. We also conducted two sets of separate experiments used to explore the impact of network connectivity and data order to our approachConclusionsThe reported test results using both synthetic and real GRNs are promising in demonstrating the applicability, effectiveness and efficiency of the proposed approach. This is due to the fact that partial observability fits well to the problem of noisy acquisition of gene expression data as there are technological limitations to measure precisely exact expression levels of genes.



http://ift.tt/2u70EAC

Using computational theory to constrain statistical models of neural data

Publication date: October 2017
Source:Current Opinion in Neurobiology, Volume 46
Author(s): Scott W Linderman, Samuel J Gershman
Computational neuroscience is, to first order, dominated by two approaches: the 'bottom-up' approach, which searches for statistical patterns in large-scale neural recordings, and the 'top-down' approach, which begins with a theory of computation and considers plausible neural implementations. While this division is not clear-cut, we argue that these approaches should be much more intimately linked. From a Bayesian perspective, computational theories provide constrained prior distributions on neural data—albeit highly sophisticated ones. By connecting theory to observation via a probabilistic model, we provide the link necessary to test, evaluate, and revise our theories in a data-driven and statistically rigorous fashion. This review highlights examples of this theory-driven pipeline for neural data analysis in recent literature and illustrates it with a worked example based on the temporal difference learning model of dopamine.



http://ift.tt/2uHdOHF

Very low emissions of airborne particulate pollutants measured from two municipal solid waste incineration plants in Switzerland

Publication date: October 2017
Source:Atmospheric Environment, Volume 166
Author(s): Ari Setyan, Michael Patrick, Jing Wang
A field campaign has been performed in two municipal solid waste incineration (MSWI) plants in Switzerland, at Hinwil (ZH) and Giubiasco (TI). The aim was to measure airborne pollutants at different locations of the abatement systems (including those released from the stacks into the atmosphere) and at a near-field (∼1 km) downwind site, in order to assess the efficiency of the abatement systems and the environmental impact of these plants.During this study, we measured the particle number concentration with a condensation particle counter (CPC), and the size distribution with a scanning mobility particle sizer (SMPS) and an aerodynamic particle sizer (APS). We also sampled particles on filters for subsequent analyses of the morphology, size and elemental composition with a scanning electron microscope coupled to an energy dispersive X-ray spectroscope (SEM/EDX), and of water soluble ions by ion chromatography (IC). Finally, volatile organic compounds (VOCs) were sampled on adsorbing cartridges and analyzed by thermal desorption-gas chromatography/mass spectrometry (TD-GC/MS), and a portable gas analyzer was used to monitor NO, SO2, CO, CO2, and O2.The particle concentration decreased significantly at two locations of the plants: at the electrostatic precipitator and the bag-house filter. The particle concentrations measured at the stacks were very low (<100 #/cm³), stressing the efficiency of the abatement system of the two plants. At Hinwil, particles sampled at the stack were mainly constituted of NaCl and KCl, two salts known to be involved in the corrosion process in incinerators. At Giubiasco, no significant differences were observed for the morphology and chemical composition of the particles collected in the ambient background and at the downwind site, suggesting that the incineration plant released very limited amounts of particles to the surrounding areas.

Graphical abstract

http://ift.tt/2u8GAPN

Complementary online aerosol mass spectrometry and offline FT-IR spectroscopy measurements: Prospects and challenges for the analysis of anthropogenic aerosol particle emissions

Publication date: October 2017
Source:Atmospheric Environment, Volume 166
Author(s): Peter Faber, Frank Drewnick, Reinhard Bierl, Stephan Borrmann
The aerosol mass spectrometer (AMS) is well established in investigating highly time-resolved dynamics of submicron aerosol chemical composition including organic aerosol (OA). However, interpretation of mass spectra on molecular level is limited due to strong fragmentation of organic substances and potential reactions inside the AMS ion chamber. Results from complementary filter-based FT-IR absorption measurements were used to explain features in high-resolution AMS mass spectra of different types of OA (e.g. cooking OA, cigarette smoking OA, wood burning OA). Using this approach some AMS fragment ions were validated in this study as appropriate and rather specific markers for a certain class of organic compounds for all particle types under investigation. These markers can therefore be used to get deeper insights in the chemical composition of OA based on AMS mass spectra in upcoming studies. However, the specificity of other fragment ions such as C2H4O2⁺ (m/z 60.02114) remains ambiguous. In such cases, complementary FT-IR measurements allow the interpretation of highly time-resolved AMS mass spectra at the level of molecular functional groups. Furthermore, this study discusses the challenges in reducing inorganic interferences (e.g. from water and ammonium salts) in FT-IR spectra of atmospheric aerosols to decrease spectral uncertainties for better comparisons and, thus, to get more robust results.



http://ift.tt/2u7QTUa

Size distributions of hydrophilic and hydrophobic fractions of water-soluble organic carbon in an urban atmosphere in Hong Kong

Publication date: October 2017
Source:Atmospheric Environment, Volume 166
Author(s): Nijing Wang, Jian Zhen Yu
Water-soluble organic carbon (WSOC) is a significant part of ambient aerosol and plays an active role in contributing to aerosol's effect on visibility degradation and radiation budget through its interactions with atmospheric water. Size-segregated aerosol samples in the range of 0.056–18 μm were collected using a ten-stage impactor sampler at an urban site in Hong Kong over one-year period. The WSOC samples were separated into hydrophilic (termed WSOC_h) and hydrophobic fractions (i.e., the humic-like substances (HULIS) fraction) through solid-phase extraction procedure. Carbon in HULIS accounted for 40 ± 14% of WSOC. The size distribution of HULIS was consistently characterized in all seasons with a dominant droplet mode (46–71%) and minor condensation (9.0–18%) and coarse modes (20–35%). The droplet mode had a mass median aerodynamic diameter in the range of 0.7–0.8 μm. This size mode showed the largest seasonal variation in abundance, lowest in the summer (0.41 μg/m³) and highest in the winter (3.3 μg/m³). WSOC_h also had a dominant droplet mode, but was more evenly distributed among different size modes. Inter-species correlations within the same size mode suggest that the condensation-mode HULIS was partly associated with combustion sources and the droplet-mode was strongly associated with secondary sulfate formation and biomass burning particle aging processes. There is evidence to suggest that the coarse-mode HULIS largely originated from coagulation of condensation-mode HULIS with coarse soil/sea salt particles. The formation process and possible sources of WSOC_h was more complicated and multiple than HULIS and need further investigation. Our measurements indicate that WSOC components contributed a dominant fraction of water-soluble aerosol mass in particles smaller than 0.32 μm while roughly 20–30% in the larger particles.

Graphical abstract

http://ift.tt/2tELMaJ

Understanding Immunosuppression after Sepsis

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Fatemeh Fattahi, Peter A. Ward
Following a severe primary infection or trauma, the risk of developing pneumonia increases due to acquired immune defects collectively known as sepsis-induced immunosuppression. In this issue of Immunity, Roquilly et al. (2017) show that dendritic cells and macrophages developing in the lung after the resolution of a severe infection acquire tolerogenic properties that contribute to persistent immunosuppression and susceptibility to secondary infections.

Teaser

Following a severe primary infection or trauma, the risk of developing pneumonia increases due to acquired immune defects collectively known as sepsis-induced immunosuppression. Roquilly et al. (2017) show that dendritic cells developing in the lung after the resolution of a severe infection acquire tolerogenic properties that contribute to persistent immunosuppression and susceptibility to secondary infections.


http://ift.tt/2uGPVzG

A Commencement for Eye Commensals

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Nancy J. Reyes, Daniel R. Saban
"Paucibacterial" levels of the normal eye surface have left immunologists wondering whether a true microbiome exists there. In this issue of Immunity, St. Leger et al. (2017) address this head-on, discovering a naturally existing commensal in mice that induces γδT cell-mediated protection from opportunistic infection.

Teaser

"Paucibacterial" levels of the normal eye surface have left immunologists wondering whether a true microbiome exists there. St. Leger et al. address this head-on, discovering a naturally existing commensal in mice that induces γδT cell-mediated protection from opportunistic infection.


http://ift.tt/2vgeZup

ILCs and T Cells Competing for Space: More Than a Numbers Game

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Christin Friedrich, Georg Gasteiger
T cell homeostasis critically depends on interleukin-7 (IL-7). In this issue of Immunity, Martin et al. (2017) provide evidence that IL-7 availability is regulated through a "cytokine sink" involving innate lymphoid cells that compete for and consume IL-7 and thereby restrict T cell homeostasis in lymphoid organs.

Teaser

T cell homeostasis critically depends on interleukin-7 (IL-7). In this issue of Immunity, Martin et al. (2017) provide evidence that IL-7 availability is regulated through a "cytokine sink" involving innate lymphoid cells that compete for and consume IL-7 and thereby restrict T cell homeostasis in lymphoid organs.


http://ift.tt/2uGSTo4

Upgrading from iMac to iMicro

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Alma N. Mohebiany, Ari Waisman
In this issue of Immunity, Takata et al. (2017) describe a novel method to differentiate macrophages from iPSCs. These cells, which they call iMacs, are similar to yolk-sac-derived macrophages and are capable of undergoing terminal differentiation into tissue-resident-like macrophages in vitro and in vivo.

Teaser

In this issue of Immunity, Takata et al. (2017) describe a novel method to differentiate macrophages from iPSCs. These cells, which they call iMacs, are similar to yolk-sac-derived macrophages and are capable of undergoing terminal differentiation into tissue-resident-like macrophages in vitro and in vivo.


http://ift.tt/2vgGCU6

Spineless Behavior of CX3CR1+ Monocytes in Response to Infection

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Paul A. Muller, Daniel Mucida
Sickness in mammals can lead to cognition deficits, although the underlying mechanisms remain elusive. In a recent Nature Medicine article, Garré et al. (2017) report that sickness-induced cortical dendritic spine loss and impaired memory formation is mediated by CX3CR1⁺ monocyte-derived TNF-α.

Teaser

Sickness in mammals can lead to cognition deficits, although the underlying mechanisms remain elusive. In a recent Nature Medicine article, Garré et al. (2017) report that sickness-induced cortical dendritic spine loss and impaired memory formation is mediated by CX3CR1⁺ monocyte-derived TNF-α.


http://ift.tt/2uGLO6J

Necroptosis: (Last) Message in a Bubble

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Peter Vandenabeele, Franck Riquet, Benjamin Cappe
RIPK3 kinase-mediated phosphorylation of MLKL pseudokinase is the execution event of necroptosis. Two independent reports—in Immunity (Yoon et al., 2017) and Cell (Gong et al., 2017)—reveal that MLKL affects homeostatic membrane trafficking and necroptosis-enhanced bubble formation involving interaction with the ESCRT machinery.

Teaser

RIPK3 kinase-mediated phosphorylation of MLKL pseudokinase is the execution event of necroptosis. Two independent reports—in Immunity (Yoon et al., 2017) and Cell (Gong et al., 2017)—reveal that MLKL affects homeostatic membrane trafficking and necroptosis-enhanced bubble formation involving interaction with the ESCRT machinery.


http://ift.tt/2vh1FWH

The P2X7 Receptor in Infection and Inflammation

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Francesco Di Virgilio, Diego Dal Ben, Alba Clara Sarti, Anna Lisa Giuliani, Simonetta Falzoni
Adenosine triphosphate (ATP) accumulates at sites of tissue injury and inflammation. Effects of extracellular ATP are mediated by plasma membrane receptors named P2 receptors (P2Rs). The P2R most involved in inflammation and immunity is the P2X7 receptor (P2X7R), expressed by virtually all cells of innate and adaptive immunity. P2X7R mediates NLRP3 inflammasome activation, cytokine and chemokine release, T lymphocyte survival and differentiation, transcription factor activation, and cell death. Ten human P2RX7 gene splice variants and several SNPs that produce complex haplotypes are known. The P2X7R is a potent stimulant of inflammation and immunity and a promoter of cancer cell growth. This makes P2X7R an appealing target for anti-inflammatory and anti-cancer therapy. However, an in-depth knowledge of its structure and of the associated signal transduction mechanisms is needed for an effective therapeutic development.

Teaser

Extracellular ATP is a common constitutent of the inflammatory milieu, where it modulates immune cell responses by activating a family of plasma membrane receptors named P2. In this review, Di Virgilio et al. discuss the central role played by the P2X7 receptor in promoting inflammation and driving innate and adaptive immunity.


http://ift.tt/2uH1Dur

Immunology of Food Allergy

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Leticia Tordesillas, M. Cecilia Berin, Hugh A. Sampson
Many consider food allergy as the "second wave" of the allergy epidemic following the "first wave" of respiratory allergy, i.e., asthma and allergic rhinitis, plaguing westernized countries, with up to 8% of young children and 2%–3% of adults in the United States now affected by hypersensitivity reactions to various foods. In the past decade, there have been great strides in our understanding of the underlying immunopathogenesis of these disorders, which have led to improved diagnostic techniques, management strategies, and therapeutic approaches. Here we will review the most recent understanding of basic mechanisms underlying IgE-mediated food allergies and novel therapeutic approaches under investigation for both the prevention and treatment of IgE-mediated food allergies.

Teaser

Food allergies have increased exponentially in the last decades. Tordesillas et al. review the immune mechanisms of sensitization to foods and recent developments in the prevention of food allergies. In addidtion, they discuss efficacy of antigen-specific immunotherapies as well as other emerging therapeutic approaches.


http://ift.tt/2vgVLoO

Hypoxia-Sensitive COMMD1 Integrates Signaling and Cellular Metabolism in Human Macrophages and Suppresses Osteoclastogenesis

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Koichi Murata, Celestia Fang, Chikashi Terao, Eugenia G. Giannopoulou, Ye Ji Lee, Min Joon Lee, Se-Hwan Mun, Seyeon Bae, Yu Qiao, Ruoxi Yuan, Moritoshi Furu, Hiromu Ito, Koichiro Ohmura, Shuichi Matsuda, Tsuneyo Mimori, Fumihiko Matsuda, Kyung-Hyun Park-Min, Lionel B. Ivashkiv
Hypoxia augments inflammatory responses and osteoclastogenesis by incompletely understood mechanisms. We identified COMMD1 as a cell-intrinsic negative regulator of osteoclastogenesis that is suppressed by hypoxia. In human macrophages, COMMD1 restrained induction of NF-κB signaling and a transcription factor E2F1-dependent metabolic pathway by the cytokine RANKL. Downregulation of COMMD1 protein expression by hypoxia augmented RANKL-induced expression of inflammatory and E2F1 target genes and downstream osteoclastogenesis. E2F1 targets included glycolysis and metabolic genes including CKB that enabled cells to meet metabolic demands in challenging environments, as well as inflammatory cytokine-driven target genes. Expression quantitative trait locus analysis linked increased COMMD1 expression with decreased bone erosion in rheumatoid arthritis. Myeloid deletion of Commd1 resulted in increased osteoclastogenesis in arthritis and inflammatory osteolysis models. These results identify COMMD1 and an E2F-metabolic pathway as key regulators of osteoclastogenic responses under pathological inflammatory conditions and provide a mechanism by which hypoxia augments inflammation and bone destruction.

Graphical abstract

Teaser

Pathways that promote osteoclastogenesis are well characterized but less is known about negative regulators that suppress pathological bone loss. Murata et al. identify COMMD1 as an inhibitor of osteoclastogenesis that restrains NF-κB- and E2F1-CKB-mediated metabolic pathways in macrophages.


http://ift.tt/2uGRAFx

Peroxisome-Mediated Metabolism Is Required for Immune Response to Microbial Infection

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Francesca Di Cara, Avinash Sheshachalam, Nancy E. Braverman, Richard A. Rachubinski, Andrew J. Simmonds
The innate immune response is critical for animal homeostasis and is conserved from invertebrates to vertebrates. This response depends on specialized cells that recognize, internalize, and destroy microbial invaders through phagocytosis. This is coupled to autonomous or non-autonomous cellular signaling via reactive oxygen species (ROS) and cytokine production. Lipids are known signaling factors in this process, as the acute phase response of macrophages is accompanied by systemic lipid changes that help resolve inflammation. We found that peroxisomes, membrane-enclosed organelles central to lipid metabolism and ROS turnover, were necessary for the engulfment of bacteria by Drosophila and mouse macrophages. Peroxisomes were also required for resolution of bacterial infection through canonical innate immune signaling. Reduced peroxisome function impaired the turnover of the oxidative burst necessary to fight infection. This impaired response to bacterial challenge affected cell and organism survival and revealed a previously unknown requirement for peroxisomes in phagocytosis and innate immunity.

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Teaser

Peroxisomes are organelles involved in lipid metabolism and reactive oxygen species turnover. Di Cara et al. now show that peroxisomes are required to resolve microbial infection by innate immunity. Peroxisomes assist in the progression of phagocytosis and activate innate immune signaling to promote survival in the face of microbial challenge.


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Local Modulation of Antigen-Presenting Cell Development after Resolution of Pneumonia Induces Long-Term Susceptibility to Secondary Infections

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Antoine Roquilly, Hamish E.G. McWilliam, Cedric Jacqueline, Zehua Tian, Raphael Cinotti, Marie Rimbert, Linda Wakim, Irina Caminschi, Mireille H. Lahoud, Gabrielle T. Belz, Axel Kallies, Justine D. Mintern, Karim Asehnoune, Jose A. Villadangos
Lung infections cause prolonged immune alterations and elevated susceptibility to secondary pneumonia. We found that, after resolution of primary viral or bacterial pneumonia, dendritic cells (DC), and macrophages exhibited poor antigen-presentation capacity and secretion of immunogenic cytokines. Development of these "paralyzed" DCs and macrophages depended on the immunosuppressive microenvironment established upon resolution of primary infection, which involved regulatory T (Treg) cells and the cytokine TGF-β. Paralyzed DCs secreted TGF-β and induced local Treg cell accumulation. They also expressed lower amounts of IRF4, a transcription factor associated with increased antigen-presentation capacity, and higher amounts of Blimp1, a transcription factor associated with tolerogenic functions, than DCs present during primary infection. Blimp1 expression in DC of humans suffering sepsis or trauma correlated with severity and complicated outcomes. Our findings describe mechanisms underlying sepsis- and trauma-induced immunosuppression, reveal prognostic markers of susceptibility to secondary infections and identify potential targets for therapeutic intervention.

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Teaser

Following a severe primary infection, the risk of developing pneumonia increases due to acquired immune defects collectively known as sepsis-induced immunosuppression. Roquilly et al. show that resolution of the primary infection changed the local environment, leading to the development of DCs and macrophages that are functionally impaired in terms of T cell activation, and instead exhibit tolerogenic properties that contribute to immune suppression.


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The Fc Domain of Immunoglobulin Is Sufficient to Bridge NK Cells with Virally Infected Cells

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Hong-Sheng Dai, Nathaniel Griffin, Chelsea Bolyard, Hsiaoyin Charlene Mao, Jianying Zhang, Timothy P. Cripe, Tadahiro Suenaga, Hisashi Arase, Ichiro Nakano, E.A. Chiocca, Balveen Kaur, Jianhua Yu, Michael A. Caligiuri
Clearance of pathogens or tumor cells by antibodies traditionally requires both Fab and Fc domains of IgG. Here, we show the Fc domain of IgG alone mediates recognition and clearance of herpes simplex virus (HSV1)-infected cells. The human natural killer (NK) cell surface is naturally coated with IgG bound by its Fc domain to the Fcγ receptor CD16a. NK cells utilize the Fc domain of bound IgG to recognize gE, an HSV1-encoded glycoprotein that also binds the Fc domain of IgG but at a site distinct from CD16a. The bridge formed by the Fc domain between the HSV1-infected cell and the NK cell results in NK cell activation and lysis of the HSV1-infected cell in the absence of HSV1-specific antibody in vitro and prevents fatal HSV1 infection in vivo. This mechanism also explains how bacterial IgG-binding proteins regulate NK cell function and may be broadly applicable to Fcγ-receptor-bearing cells.

Teaser

IgG conventionally utilizes its Fab and Fc domains to engage antigens and immune effector cells, respectively. Dai et al. show that the Fc domain alone allows CD16+ NK cells to recognize and lyse virus-infected cells that express IgG-binding proteins.


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Interleukin-7 Availability Is Maintained by a Hematopoietic Cytokine Sink Comprising Innate Lymphoid Cells and T Cells

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Christopher E. Martin, Darina S. Spasova, Kwesi Frimpong-Boateng, Hee-Ok Kim, Minji Lee, Kwang Soon Kim, Charles D. Surh
Interleukin-7 (IL-7) availability determines the size and proliferative state of the resting T cell pool. However, the mechanisms that regulate steady-state IL-7 amounts are unclear. Using experimental lymphopenic mouse models and IL-7-induced homeostatic proliferation to measure IL-7 availability in vivo, we found that radioresistant cells were the source of IL-7 for both CD4⁺ and CD8⁺ T cells. Hematopoietic lineage cells, although irrelevant as a source of IL-7, were primarily responsible for limiting IL-7 availability via their expression of IL-7R. Unexpectedly, innate lymphoid cells were found to have a potent influence on IL-7 amounts in the primary and secondary lymphoid tissues. These results demonstrate that IL-7 homeostasis is achieved through consumption by multiple subsets of innate and adaptive immune cells.

Teaser

IL-7 availability for lymphocytes is thought to be set by the amount of IL-7 production by radioresistant cells, such as fibroblastic reticular cells, and consumption by IL-7R⁺ hematopoietic cells. Martin et al. confirm this finding and also find that ILCs can outcompete T cells for IL-7 by resisting downregulation of IL-7R through differential modulation of transcription factor FOXO1, which regulates IL-7R expression.


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Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function

Publication date: 18 July 2017
Source:Immunity, Volume 47, Issue 1
Author(s): Kazuyuki Takata, Tatsuya Kozaki, Christopher Zhe Wei Lee, Morgane Sonia Thion, Masayuki Otsuka, Shawn Lim, Kagistia Hana Utami, Kerem Fidan, Dong Shin Park, Benoit Malleret, Svetoslav Chakarov, Peter See, Donovan Low, Gillian Low, Marta Garcia-Miralles, Ruizhu Zeng, Jinqiu Zhang, Chi Ching Goh, Ahmet Gul, Sandra Hubert, Bernett Lee, Jinmiao Chen, Ivy Low, Nurhidaya Binte Shadan, Josephine Lum, Tay Seok Wei, Esther Mok, Shohei Kawanishi, Yoshihisa Kitamura, Anis Larbi, Michael Poidinger, Laurent Renia, Lai Guan Ng, Yochai Wolf, Steffen Jung, Tamer Önder, Evan Newell, Tara Huber, Eishi Ashihara, Sonia Garel, Mahmoud A. Pouladi, Florent Ginhoux
Tissue macrophages arise during embryogenesis from yolk-sac (YS) progenitors that give rise to primitive YS macrophages. Until recently, it has been impossible to isolate or derive sufficient numbers of YS-derived macrophages for further study, but data now suggest that induced pluripotent stem cells (iPSCs) can be driven to undergo a process reminiscent of YS-hematopoiesis in vitro. We asked whether iPSC-derived primitive macrophages (iMacs) can terminally differentiate into specialized macrophages with the help of growth factors and organ-specific cues. Co-culturing human or murine iMacs with iPSC-derived neurons promoted differentiation into microglia-like cells in vitro. Furthermore, murine iMacs differentiated in vivo into microglia after injection into the brain and into functional alveolar macrophages after engraftment in the lung. Finally, iPSCs from a patient with familial Mediterranean fever differentiated into iMacs with pro-inflammatory characteristics, mimicking the disease phenotype. Altogether, iMacs constitute a source of tissue-resident macrophage precursors that can be used for biological, pathophysiological, and therapeutic studies.

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Teaser

Yolk-sac (YS) embryonic macrophages contribute to tissue-resident macrophages but remain difficult to study because of their stage-dependent limited availability. Takata et al. demonstrate that iPSCs can generate YS macrophage-like cells (iMacs) that differentiate into functional tissue-resident macrophage-like cells upon receiving organ-specific cues, thus providing a platform for modeling tissue-resident macrophages.


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Tendon Transfer to Restore the Extension of the Thumb Using the Extensor Carpi Radialis Brevis: A Long-Term Follow-Up

The study aimed to investigate the long-term functional and clinical outcomes of a tendon transfer to restore the extension of the thumb using the extensor carpi radialis brevis.

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“Reverse expansion”: A new technique of breast reconstruction with autologous tissue

The treatment for breast cancer is sometimes long and requires a multidisciplinary approach. In 2010, in our centre we began to perform fat grafting for breast reconstruction using the so-called "reverse expansion" technique. This consists in the insertion of a skin expander during mastectomy, in its expansion and then in its gradual deflation in the surgical theatre during fat grafting. We have performed a complete breast reconstruction in 57 patients using reverse expansion. We have harvested fat in the fat excess areas using a normal liposuction cannula.

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Echocardiography and passive leg raising in the postoperative period: A prospective observational study.

BACKGROUND: Signs of hypovolaemia are frequent in the postoperative period, but not all patients need or respond to fluid administration. An increase in cardiac output (CO) after passive leg raising (PLR) has been demonstrated to be useful as a volume response predictor in non-surgical, spontaneously breathing patients. OBJECTIVE: The objective of this study was to evaluate the accuracy of transthoracic echocardiography after PLR to predict fluid responsiveness in post-surgical patients. DESIGN: A prospective observational study. SETTING: A tertiary hospital between January and July 2015. PATIENTS: Fifty-one spontaneously breathing postoperative patients with suspected hypovolaemia (arterial hypotension, oliguria, tachycardia or delayed capillary refill) were considered for the study. INTERVENTION: Demographic and personal data were collected, as well as heart rate variations, mean arterial pressure during PLR and after administering 500 ml of Ringer's lactate solution. CO was measured by transthoracic echocardiography. MAIN OUTCOME MEASURES: The primary outcome was measurement of CO before and after PLR and Ringer's lactate administration. RESULTS: Forty-one patients were included in the study (six patients were excluded because of a poor echocardiographic window and four because of misalignment of the Doppler and outflow tract of the left ventricle). Twenty-two patients (54%) were considered responders to fluid therapy, with an increase of stroke volume greater than or equal to 15% after 500 ml lactated Ringer's infusion. The highest area under the curve was found for an increase in CO (0.91 +/- 0.05; 95% confidence interval 0.78 to 0.97). An increase in CO greater than 11% after the PLR manoeuvre predicts a volume response with 68% sensitivity and 100% specificity. CONCLUSION: This is the first study showing that measurement of CO after PLR can predict volume response in spontaneously breathing postoperative patients. (C) 2017 European Society of Anaesthesiology

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Anaesthetic management of patients with myopathies.

: The anaesthetic management of patients with myopathies is challenging. Considering the low incidence and heterogeneity of these disorders, most anaesthetists are unfamiliar with key symptoms, associated co-morbidities and implications for anaesthesia. The pre-anaesthetic assessment aims at the detection of potentially undiagnosed myopathic patients and, in case of known or suspected muscular disease, on the quantification of disease progression. Ancillary testing (e.g. echocardiography, ECG, lung function testing etc.) is frequently indicated, even at a young patient age. One must differentiate between myopathies associated with malignant hyperthermia (MH) and those that are not, as this has significant impact on preoperative preparation of the anaesthesia workstation and pharmacologic management. Only few myopathies are clearly associated with MH. If a regional anaesthetic technique is not possible, total intravenous anaesthesia is considered the safest approach for most patients with myopathies to avoid anaesthesia-associated rhabdomyolysis. However, the use of propofol in patients with mitochondrial myopathies may be problematic, considering the risk for propofol-infusion syndrome. Succinylcholine is contra-indicated in all patients with myopathies. Following an individual risk/benefit evaluation, the use of volatile anaesthetics in several non-MH-linked myopathies (e.g. myotonic syndromes, mitochondrial myopathies) is considered to be well tolerated. Perioperative monitoring should specifically focus on the cardiopulmonary system, the level of muscular paralysis and core temperature. Given the high risk of respiratory compromise and other postoperative complications, patients need to be closely monitored postoperatively. (C) 2017 European Society of Anaesthesiology

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Fate of antimicrobial resistance genes in response to application of poultry and swine manure in simulated manure-soil microcosms and manure-pond microcosms

Abstract

This study aimed to determine the occurrence, abundance, and fate of nine important antimicrobial resistance genes (ARGs) (sul1, sul2, tetB, tetM, ermB, ermF, fexA, cfr, and Intl1) in the simulated soil and pond microcosms following poultry and swine manure application. Absolute quantitative PCR method was used to determine the gene copies. The results were modeled as a logarithmic regression (N = mlnt + b) to explore the fate of target genes. Genes sul1, Intl1, sul2, and tetM had the highest abundance following the application of the two manure types. The logarithmic regression model fitted the results well (R ² values up to 0.99). The reduction rate of all genes (except for the genes fexA and cfr) in manure-pond microcosms was faster than those in manure-soil microcosms. Importantly, sul1, intl1, sul2, and tetM had the lowest reduction rates in all the samples and the low reduction rates of tetM was the first time to be reported. These results indicated that ARG management should focus on using technologies for the ARG elimination before the manure applications rather than waiting for subsequent attenuation in soil or water, particularly the ARGs (such as sul1, intl1, sul2, and tetM investigated in this study) that had high abundance and low reduction rate in the soil and water after application of manure.

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LncRNA HOTAIR alleviates rheumatoid arthritis by targeting miR-138 and inactivating NF-κB pathway

Publication date: September 2017
Source:International Immunopharmacology, Volume 50
Author(s): Hong-ju Zhang, Qiao-feng Wei, Shu-jun Wang, Hong-jie Zhang, Xiu-ying Zhang, Qin Geng, Yan-hui Cui, Xiu-hua Wang
Rheumatoid arthritis (RA) is a chronic and autoimmune-mediated inflammatory disease. We aimed to investigate the regulation of lncRNA HOTAIR in LPS-treated chondrocytes and RA mouse. Our results showed that HOTAIR expression was significantly reduced in LPS-treated chondrocytes. The HOTAIR was then over-expressed in chondrocytes by transfecting recombinant lentivirus carrying sequences encoding HOTAIR. The LPS-induced reduction of cell proliferation rate and production of two inflammatory factors interleukin (IL)-17, IL-23 were markedly inhibited. Enforced expression of HOTAIR also led to the upregulation of proliferation-related protein Ki67 and proliferating cell nuclear antigen (PCNA). Moreover, a negative correlation was detected between the expression of HOTAIR and microRNA (miR)-138, and the expression of miR-138 was significantly increased in LPS-induced chondrocytes. The effects of HOTAIR over-expression on the proliferation and inflammation were partly reversed by miR-138 overexpression. Furthermore, the overexpression of HOTAIR significantly inhibited the activation of nuclear transcription factor-κB (NF-κB) in LPS-treated chondrocytes by suppressing p65 to cell nucleus, resulting in the down-regulation of IL-1β and tumor necrosis factor (TNF)-α. In addition, the in vivo experiments exhibited that overexpression of HOTAIR increased cell proliferation and inhibited inflammation in RA rats, which were demonstrated by upregulation of Ki67 and PCNA, reduced CD4⁺IL-17⁺,CD4⁺IL-23⁺ cells, and down-regulation of p-p65, IL-1β and TNF-α. In summary, our study suggests HOTAIR plays a protective role in RA by increasing proliferation rate and inhibiting inflammation, which may be related with the regulation of miR-138 expression and NF-κB signaling pathway. These results suggest that the regulation of HOTAIR may be a promising therapeutic strategy for RA.

Graphical abstract

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Cultural patterns within and outside of the post-contact Great Plains as revealed by parfleche characteristics: Implications for areal arrangements in artifactual data

Publication date: December 2017
Source:Journal of Anthropological Archaeology, Volume 48
Author(s): Stephen J. Lycett
For some time it has been recognized that areal arrangements in ethnographic data might help archaeologists understand equivalent arrangements in artifactual data, especially in anthropologically relevant terms. Equally, ethnographic data have shown that material-culture patterns do not necessarily conveniently map discrete "peoples" or ethnolinguistic communities. However, the question still persists as to whether areal patterns in artifactual data represent anthropologically important information, and if so, how. Ethnographically, studies of these issues have tended to adopt two approaches. Some studies have examined areal patterning across broad geographic areas in terms of presences and absences of particular artifacts or suites of artifacts. Alternatively, studies have looked at variation in the stylistic traits of particular artifacts, but over a relatively more discrete geographic range, typically a sub-region defined on the basis of other cultural and/or ecological distinctions. Here, in this study a different approach is taken, whereupon variations in the inter-tribe attributes of a singular artifact class (post-contact-era "parfleches" or decorated rawhide bags) are examined over a wide geographic area (western North America). Multivariate statistical analyses demonstrate that among-tribe variation in parfleche characteristics most strongly conforms to three geographic stylistic regions and, moreover, that these three stylistic regions disregard linguistic affiliations and "culture area" designations. These trait-level patterns conform to documented trade patterns across the study area, explaining why these areal patterns disregard distinctions made on other criteria. Ultimately, the study demonstrates ethnographically the value of contrasting areal patterns based on discrete artifactual distinctions (i.e., presence and absence of particular artifacts) versus broader-scale, but trait-level, patterns in artifacts common across these different areas.

Graphical abstract

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Key indicator tools for shallow slope failure assessment using soil chemical property signatures and soil colour variables

Abstract

Slope failure has become a major concern in Malaysia due to the rapid development and urbanisation in the country. It poses severe threats to any highway construction industry, residential areas, natural resources and tourism activities. The extent of damages that resulted from this catastrophe can be lessened if a long-term early warning system to predict landslide prone areas is implemented. Thus, this study aims to characterise the relationship between Oxisols properties and soil colour variables to be manipulated as key indicators to forecast shallow slope failure. The concentration of each soil property in slope soil was evaluated from two different localities that consist of 120 soil samples from stable and unstable slopes located along the North-South Highway (PLUS) and East-West Highway (LPT). Analysis of variance established highly significant difference (P < 0.0001) between the locations, the total organic carbon (TOC), soil pH, cation exchange capacity (CEC), soil texture, soil chromaticity and all combinations of interactions. The overall CIELAB analysis leads to the conclusion that the CIELAB variables lightness L*, c* (Chroma) and h* (Hue) provide the most information about soil colour and other related soil properties. With regard to the relationship between colour variables and soil properties, the analysis detected that soil texture, organic carbon, iron oxide and aluminium concentration were the key factors that strongly correlate with soil colour variables at the studied area. Indicators that could be used to predict shallow slope failure were high value of L*(62), low values of c* (20) and h* (66), low concentration of iron (53 mg kg⁻¹) and aluminium oxide (37 mg kg⁻¹), low soil TOC (0.5%), low CEC (3.6 cmol/kg), slightly acidic soil pH (4.9), high amount of sand fraction (68%) and low amount of clay fraction (20%).

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Cutaneous Indeterminate Cell Histiocytosis of Donor Origin After Allogeneic Hematopoietic Stem-Cell Transplantation.

Allogeneic hematopoietic stem-cell transplantation and solid-organ transplantation are associated with an increased risk of secondary neoplasms. Indeterminate cell histiocytosis (ICH) is a rare disease composed of so-called indeterminate cells, an alleged cutaneous dendritic cell subset displaying histological and some ultrastructural and immunophenotypic features of Langerhans cells but lacking Birbeck granules. We report a case of cutaneous ICH occurring after allogeneic hematopoietic stem-cell transplantation for a myelodysplastic syndrome in a 56-year-old man. Microsatellite analysis demonstrated that the neoplastic cells were derived from the donor's hematopoietic system. This case broadens the spectrum of complications after stem-cell transplantation and demonstrates that cutaneous ICH in the setting of myelodysplastic syndromes may have a nonrelated origin to dysplastic myeloid cells. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Systematic Review of the Use of 3-Dimensional Printing in Surgical Teaching and Assessment

Publication date: Available online 17 July 2017
Source:Journal of Surgical Education
Author(s): Benjamin Langridge, Sheikh Momin, Ben Coumbe, Evelina Woin, Michelle Griffin, Peter Butler
ObjectiveThe use of 3-dimensional (3D) printing in medicine has rapidly expanded in recent years as the technology has developed. The potential uses of 3D printing are manifold. This article provides a systematic review of the uses of 3D printing within surgical training and assessment.MethodsA structured literature search of the major literature databases was performed in adherence to PRISMA guidelines. Articles that met predefined inclusion and exclusion criteria were appraised with respect to the key objectives of the review and sources of bias were analysed.ResultsOverall, 49 studies were identified for inclusion in the qualitative analysis. Heterogeneity in study design and outcome measures used prohibited meaningful meta-analysis. 3D printing has been used in surgical training across a broad range of specialities but most commonly in neurosurgery and otorhinolaryngology. Both objective and subjective outcome measures have been studied, demonstrating the usage of 3D printed models in training and education. 3D printing has also been used in anatomical education and preoperative planning, demonstrating improved outcomes when compared to traditional educational methods and improved patient outcomes, respectively.Conclusions3D printing technology has a broad range of potential applications within surgical education and training. Although the field is still in its relative infancy, several studies have already demonstrated its usage both instead of and in addition to traditional educational methods.



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Assessing Interest and Barriers for Resident and Faculty Involvement in Global Surgery

Publication date: Available online 17 July 2017
Source:Journal of Surgical Education
Author(s): Maija Cheung, James M. Healy, Michael R. Hall, Doruk Ozgediz
BackgroundMultiple institutions have developed international electives and sustainable global surgery initiatives to facilitate clinical, research, and outreach opportunities with hospitals in resource-poor areas. Despite increasing interest among programs, many institutions have not successfully reached potential involvement.ObjectiveThis study evaluates the experiences of Yale residents and faculty, measures interest in the development of an international surgical elective, and enumerates barriers to developing or participating in these opportunities. This was performed to develop a formalized elective and assess interest and capacity for surgical global health initiatives, as a seemingly increasing number of trainee applicants and residents were expressing interest in working in resource-poor settings.MethodsElectronic survey of Yale Surgery residents and faculty analyzed using SPSS and Graphpad Prism.ResultsAmong residents, previous global experience correlates with current interest in international opportunities, with 100% remaining interested, and 78% of those without prior experience also expressing interest (p = 0.018). Barriers to pursuing these activities included the use of vacation time, funding, scheduling, family obligations, and concern for personal safety. Among faculty, 28% of respondents have been involved internationally, and most (86%) expressed interest in additional opportunities and all were willing to take residents. Barriers to faculty participation included funding, relative value unit target reduction, protected time, and the desire for institutional support for such activities.ConclusionsA substantial proportion of residents and faculty have experience in global health and motivation to pursue additional opportunities. The main barriers to participation are not a lack of interest, but rather needs for funding support, protected time, and institutional recognition of academic contributions. These findings are being used to develop a global surgery elective and establish long-term partnerships with international colleagues.



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The Quality In-Training Initiative: Giving Residents Data to Learn Clinical Effectiveness

Publication date: Available online 17 July 2017
Source:Journal of Surgical Education
Author(s): Morgan M. Sellers, Matt Fordham, Craig W. Miller, Clifford Y. Ko, Rachel R. Kelz
BackgroundTraining programs are expected to provide clinical outcomes data to residents. Few systems have the necessary infrastructure. We evaluated initial adoption and use of the Quality In-Training Initiative (QITI) platform linking National Surgical Quality Improvement Program (NSQIP) data to trainees.Study DesignProportions of Accreditation Council for Graduate Medical Education general surgery residency programs with differing levels of NSQIP and QITI affiliation were calculated and program characteristics were compared. All NSQIP sites that captured QITI custom field data from July 2013 to June 2016 were included in case analysis. Differences in case collection were compared between participating (P) sites that actively participated in QITI and nonparticipating (NP) sites that did not. Resident participation by procedure type was examined.ResultsOf 268 accredited general surgery residency programs, 92% (n = 248) is affiliated with a NSQIP hospital and 61% of all clinical months is spent at NSQIP sites. For 42% of all programs (n = 114), the primary teaching hospital is affiliated with the QITI. In all, 74 P sites and 89 NP sites captured a total of 417,816 cases. The median number of cases captured per site was statistically higher for P sites (3063) compared with NP sites (2307, p < 0.001).A total of 68.3% of all cases captured had resident participation indicated by postgraduate year (n = 285,469). The most common procedures with resident participation were laparoscopic appendectomy (n = 17,082, 6.0%) and laparoscopic cholecystectomy (n = 15,502, 5.4%). Percentage coverage rates ranged from 17.3% to 91.8%.ConclusionMost general surgery rotations are at NSQIP sites. Identifying resident participation in captured NSQIP cases is feasible on a large scale. Captured cases reflect national case-mix. The platform has the potential to collect data on institutional and program-level variation in resident operative experience that may be used to improve training.



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