bluuebunny/crossref_metadata_2025 huggingface dataset:
Protease inhibitors stimulate hematopoiesis and decrease apoptosis and ICE expression in CD34+ cells
Authors: Sloand Elaine M. , Maciejewski Jaroslaw , Kumar Princy , Kim Sonnie , Chaudhuri Aniruddho , Young Neal
Published: October 2019

Highly active retroviral therapy has been associated with a decline in the frequency of cytopenia in patients with human immunodeficiency virus (HIV) infection. This may result from lower hematologic toxicity of newer antiviral drugs and their increased efficacy against HIV-1. Protease inhibitors, in addition to their effects on HIV replication, appear to affect various cellular functions. Recently, it was reported that ritonavir inhibited caspase-1 expression in normal CD4+ cells. It was hypothesized that protease inhibitors may improve hematopoietic function owing to their direct effects on the bone marrow progenitor cells. When ritonavir was added to methylcellulose cultures of bone marrow cells from HIV-infected patients and normal controls, colony formation increased 2.4-fold (n = 5) in control cultures and 4-fold (n = 5) in cultures of cells from HIV-infected patients. In the presence of ritonavir, cultures of CD34+ cells showed markedly decreased apoptosis in comparison with untreated cultures (45% decrease in apoptotic cell number; n = 6). A synthetic inhibitor of caspase 1 (Ac-Tyr-Val-Ala-Asp-aldehyde [single-letter amino acid codes]), which inhibits activation of several caspases including CPP32 and interleukin 1β–converting enzyme (ICE or caspase 1), also decreased the rate of apoptosis and enhanced colony formation by progenitor cells derived from HIV-infected patients (3-fold; n = 5). In ritonavir-treated samples derived from HIV-infected individuals, the number of cells expressing ICE also decreased. In conclusion, HIV protease inhibitors may, by blocking the caspase-dependent apoptotic pathway, overcome inhibition of hematopoiesis seen in patients with HIV infection, an effect unrelated to their antiviral activity.
Induction of decay-accelerating factor by thrombin through a protease-activated receptor 1 and protein kinase C–dependent pathway protects vascular endothelial cells from complement-mediated injury
Authors: Lidington Elaine A. , Haskard Dorian O. , Mason Justin C.
Published: October 2019

There is increasing evidence for functional crosstalk between inflammatory and thrombotic pathways in inflammatory vascular diseases such as atherosclerosis and vasculitis. Thus, complement activation on the endothelial cell (EC) surface during inflammation may generate thrombin via the synthesis of tissue factor. We explored the hypothesis that thrombin induces EC expression of the complement-regulatory proteins decay-accelerating factor (DAF), membrane cofactor protein (MCP), and CD59 and that this maintains vascular integrity during coagulation associated with complement activation. Thrombin increased DAF expression on the surface of ECs by 4-fold in a dose- and time-dependent manner as measured by flow cytometry. DAF up-regulation was first detectable at 6 hours and maximal 24 hours poststimulation, whereas no up-regulation of CD59 or MCP was seen. Thrombin-induced expression required increased DAF messenger RNA and de novo protein synthesis. The response depended on activation of protease-activated receptor 1 (PAR1) and was inhibited by pharmacologic antagonists of protein kinase C (PKC), p38 and p42/44 mitogen-activated protein kinase, and nuclear factor-κB. The increased DAF expression was functionally relevant because it significantly reduced C3 deposition and complement-mediated EC lysis. Thus, thrombin—generated at inflammatory sites in response to complement activation—is a physiologic agonist for the PKC-dependent pathway of DAF regulation, thereby providing a negative feedback loop protecting against thrombosis in inflammation.
Nonsense mutations in the human β-globin gene lead to unexpected levels of cytoplasmic mRNA accumulation
Authors: Romão Luı́sa , Inácio Ângela , Santos Susana , Ávila Madalena , Faustino Paula , Pacheco Paula , Lavinha João
Published: October 2019

Generally, nonsense codons 50 bp or more upstream of the 3′-most intron of the human β-globin gene reduce mRNA abundance. In contrast, dominantly inherited β-thalassemia is frequently associated with nonsense mutations in the last exon. In this work, murine erythroleukemia (MEL) cells were stably transfected with human β-globin genes mutated within each of the 3 exons, namely at codons 15 (TGG→TGA), 39 (C→T), or 127 (C→T). Primer extension analysis after erythroid differentiation induction showed codon 127 (C→T) mRNA accumulated in the cytoplasm at approximately 20% of the normal mRNA level. Codon 39 (C→T) mutation did not result in significant mRNA accumulation. Unexpectedly, codon 15 (TGG→TGA) mRNA accumulated at approximately 90%. Concordant results were obtained when reticulocyte mRNA from 2 carriers for this mutation was studied. High mRNA accumulation of codon 15 nonsense-mutated gene was revealed to be independent of the type of nonsense mutation and the genomic background in which this mutation occurs. To investigate the effects of other nonsense mutations located in the first exon on the mRNA level, nonsense mutations at codons 5, 17, and 26 were also cloned and stably transfected into MEL cells. After erythroid differentiation induction, mRNAs with a mutation at codon 5 or 17 were detected at high levels, whereas the mutation at codon 26 led to low mRNA levels. These findings suggest that nonsense-mediated mRNA decay is not exclusively dependent on the localization of mutations relative to the 3′-most intron. Other factors may also contribute to determine the cytoplasmic nonsense-mutated mRNA level in erythroid cells.
Bcl-2 rearrangement in patients with chronic hepatitis C associated with essential mixed cryoglobulinemia type II
Authors: Kitay-Cohen Yona , Amiel Aliza , Hilzenrat Nir , Buskila Dan , Ashur Yaffa , Fejgin Moshe , Gaber Elena , Safadi Rifaat , Tur-kaspa Ran , Lishner Michael
Published: October 2019

Hepatitis C virus (HCV) infection is found in 80% to 90% of patients with essential mixed cryoglobulinemia (EMC) type II, which is associated with monoclonal IgMk produced by monoclonal B cells. It was investigated whether bcl-2 rearrangement is associated with the clonal B-cell proliferation of EMC induced by hepatitis C. The study groups were composed of 15 patients with HCV and EMC, 12 patients with HCV without EMC, and 7 patients with chronic liver disease (CLD) unrelated to HCV. Fluorescence in situ hybridization with probes was applied to JH and to bcl-2 to study whether JH/bcl-2 translocation was present in these patients. Thirteen of 15 (86%) of patients with HCV-related EMC had the JH/bcl-2 translocation, a significantly higher rate than in HCV patients without EMC (16%; P < .001). Bcl-2 rearrangement was not detected in the patients with CLD not related to HCV. The JH/bcl2 translocation may constitute a pathogenetic link for the development of NHL in patients with HCV infection.
Diagnostic value of dominant T-cell clones in peripheral blood in 363 patients presenting consecutively with a clinical suspicion of cutaneous lymphoma
Authors: Delfau-Larue Marie-Hélène , Laroche Liliane , Wechsler Janine , Lepage Eric , Lahet Chantal , Asso-Bonnet Marianne , Bagot Martine , Farcet Jean-Pierre
Published: October 2019

It is now widely accepted that polymerase chain reaction (PCR) analysis of cutaneous T-cell clonality is of diagnostic value in cutaneous T-cell lymphomas (CTCLs) and most helpful in the diagnosis of mycosis fungoides (MF). However, the diagnostic and prognostic value of circulating clonal T cells remains unclear. We studied T-cell clonality in the peripheral blood (PB) and the cutaneous lesion, sampled at the same time, in 363 consecutively seen patients with a clinical suspicion of cutaneous lymphoma. Using a PCR technique providing a specific imprint of T-cell clones (PCRγ–denaturing gradient gel electrophoresis), we found that detection of identical circulating and cutaneous T-cell clones was associated with the diagnosis of CTCL (P < .001). Detection of circulating tumor cells in patients with MF was infrequent (12.5%), except in those with erythrodermic MF (42%; P = .003). Moreover, among the 46 patients who had identical circulating and cutaneous T-cell clones, 25 (56%) had erythroderma. The finding of a dominant clone in the PB but not in the skin was frequent, regardless of the clinicohistologic classification; it occurred in 30% of patients with CTCL, 41% with non-CTCL malignant infiltrates, and 34% with benign infiltrates. This pattern was significantly more frequent in patients over 60 years of age (P < .002), even in the CTCL group (P < .01). In conclusion, dominant T-cell clones detected in the PB of patients with MF by using a routine PCR technique are rarely tumoral and are more often related to age. A multicenter prospective study is under way to establish the prognostic value of circulating tumor cells.
Murine hematopoietic stem cell characterization and its regulation in BM transplantation
Authors: Zhao Yi , Lin Yuanguang , Zhan Yuxia , Yang Gengjie , Louie Jeffrey , Harrison David E. , Anderson W. French
Published: October 2019

Using 5-color fluorescence-activated cell sorting, we isolated a subset of murine pluripotent hematopoietic stem cells (PHSC) with the phenotype Lin− Sca+ kit+CD38+ CD34− that appears to fulfill the criteria for most primitive PHSC. In the presence of whole bone marrow (BM) competitor cells, these cells produced reconstitution in lethally irradiated primary, secondary, and tertiary murine transplant recipients over the long term. However, these cells alone could not produce reconstitution in lethally irradiated recipients. Rapid proliferation of these cells after BM transplantation required the assistance of another BM cell subset, which has the phenotype Lin− Sca+ kit+ CD38−CD34+.
Generation of murine dendritic cells from flt3-ligand–supplemented bone marrow cultures
Authors: Brasel Kenneth , De Smedt Thibaut , Smith Jeffery L. , Maliszewski Charles R.
Published: October 2019

Murine dendritic cells (DCs) can be classified into at least 2 subsets, “myeloid-related” (CD11bbright, CD8α−) and “lymphoid-related” (CD11bdull, CD8α+), but the absolute relationship between the 2 remains unclear. Methods of generating DCs from bone marrow (BM) precursors in vitro typically employ granulocyte-macrophage colony-stimulating factor (GM-CSF) as the principal growth factor, and the resultant DCs exhibit a myeloidlike phenotype. Here we describe a flt3-ligand (FL)–dependent BM culture system that generated DCs with more diverse phenotypic characteristics. Murine BM cells cultured at high density in recombinant human FL for 9 days developed into small lymphoid-sized cells, most of which expressed CD11c, CD86, and major histocompatibility complex (MHC) class II. The CD11c+ population could be divided into 2 populations on the basis of the level of expression of CD11b, which may represent the putative myeloid- and lymphoid-related subsets. The FL in vitro–derived DCs, when treated with interferon-α or lipopolysaccharide during the final 24 hours of culture, expressed an activated phenotype that included up-regulation of MHC class II, CD1d, CD8α, CD80, CD86, and CD40. The FL-derived DCs also exhibited potent antigen-processing and antigen-presenting capacity. Neutralizing anti–interleukin-6 (IL-6) antibody, but not anti–GM-CSF, significantly reduced the number of DCs generated in vitro with FL, suggesting that IL-6 has a role in the development of DCs from BM precursors. Stem cell factor, which exhibits some of the same bioactivities as FL, was unable to replace FL to promote DC development in vitro. This culture system will facilitate detailed analysis of murine DC development.
Interferon γ and interleukin 6 modulate the susceptibility of macrophages to human immunodeficiency virus type 1 infection
Authors: Zaitseva Marina , Lee Shirley , Lapham Cheryl , Taffs Rolf , King Lisa , Romantseva Tatiana , Manischewitz Jody , Golding Hana
Published: October 2019

The effect of interferon γ (IFN-γ) and interleukin 6 (IL-6) on infection of macrophages with human immunodeficiency virus type 1 (HIV-1) was investigated. By using a polymerase chain reaction–based viral entry assay and viral infectivity assay, it was demonstrated that IL-6 and IFN-γ augmented susceptibility of monocyte-derived macrophages (MDMs) to infection with T-cell tropic CXCR4-utilizing (X4) HIV-1 strains. Consistent with this finding, IFN-γ and IL-6 augmented fusion of MDMs with T-tropic envelope-expressing cells. The enhanced fusion of cytokine-treated MDMs with T-tropic envelopes was inhibited by the CXCR4 ligand, SDF-1, and by T22 peptide. IFN-γ and IL-6 did not affect expression of surface CXCR4 or SDF-1–induced Ca++ flux in MDMs. In contrast to the effect of IFN-γ on the infection of MDMs with X4 strains, IFN-γ inhibited viral entry and productive infection of MDMs with macrophage-tropic (M-tropic) HIV-1. Consistent with this finding, IFN-γ induced a decrease in fusion with M-tropic envelopes that correlated with a modest reduction in surface CCR5 and CD4 on MDMs. It was further demonstrated that macrophage inflammatory protein (MIP)-1α and MIP-β secreted by cytokine-treated MDMs augmented their fusion with T-tropic–expressing cells and inhibited their fusion with M-tropic envelope-expressing cells. These data indicate that proinflammatory cytokines, which are produced during opportunistic infections or sexually transmitted diseases, may predispose macrophages to infection with X4 strains that, in turn, could accelerate disease progression.
Chronic lymphocytic leukemia B cells inhibit spontaneous Ig production by autologous bone marrow cells: role of CD95-CD95L interaction
Authors: Sampalo Almudena , Navas Gloria , Medina Francisco , Segundo Carmen , Cámara Carmen , Brieva José A.
Published: October 2019

A variable degree of humoral immunodeficiency is a common feature in patients with B-cell chronic lymphocytic leukemia (B-CLL). The aim of this study was to explore the possibility that B-CLL cells play a direct role in this phenomenon. To this end, patients' bone marrow (BM) immunoglobulin (Ig)-secreting cells were cocultured with autologous purified B-CLL cells. The results show that tumoral cells inhibited the spontaneous IgG secretion by BM plasma cells, and this effect increased after PMA-induction of B-CLL cells. This inhibitory process was proportional to the number of B-CLL cells added and depended on cellular contact. Adhesion molecules did not appear to be involved in the cellular interaction, because the inclusion of blocking antibody to a variety of these proteins did not reverse the inhibitory phenomenon. However, the addition of monoclonal antibody that blocked the function of either CD95 or CD95L clearly reversed B-CLL cell inhibition on autologous BM plasma cells. These latter cells were shown to express CD95, and B-CLL cells contained detectable quantities of CD95L at the level of messenger RNA and protein. Annexin V–binding experiments revealed increased apoptosis of BM Ig-secreting cells when cocultured with autologous B-CLL cells. Finally, this inhibitory phenomenon might be operative in vivo because (a) there was a good correlation between the intensity of the inhibitory effect in vitro and the serum IgG level exhibited by every patient and (b) B-CLL cells also inhibited in vivo antigen-induced IgG-tetanus toxoid–secreting cells obtained from normal immunized subjects. Collectively, these data suggest that B-CLL cells inhibit autologous CD95-bearing Ig-secreting cells by the interaction with CD95L present on B-CLL cells and, hence, contribute to the state of humoral immunodeficiency that occurs in these patients.
Retinoic acid stimulates erythropoietin gene transcription in embryonal carcinoma cells through the direct repeat of a steroid/thyroid hormone receptor response element half-site in the hypoxia-response enhancer
Authors: Kambe Taiho , Tada-Kambe Junko , Kuge Yoshihiro , Yamaguchi-Iwai Yuko , Nagao Masaya , Sasaki Ryuzo
Published: October 2019

We have previously reported that expression of the erythropoietin (Epo) gene in mouse embryonal cells was not induced by hypoxia, although hypoxia induced other hypoxia-inducible genes. This study identifies retinoic acid (RA) as an inducer for Epo production in the embryonal carcinoma cell lines P19 and F9. RA induced Epo production through the transcriptional activation of the Epo gene in an oxygen-independent manner. With the use of reporter assays in P19 cells, it is shown that a direct repeat of the nuclear hormone receptor-binding motif separated by a 2-bp spacer (DR-2) in the hypoxia-response enhancer was responsible for the transcriptional activation by RA. Electrophoretic mobility shift assays show that nuclear extracts from P19 cells contained RA receptor complexes that bound to DR-2. In human hepatoma Hep3B cells, an orphan receptor, hepatocyte nuclear factor-4, strongly augmented hypoxic induction of the Epo gene in cooperation with hypoxia-inducible factor-1 (HIF-1) by binding to DR-2, whereas in P19 cells, the interaction of RA receptors with DR-2 was sufficient for RA-induced transcriptional activation of the Epo gene without the requirement of the HIF-1 site. These results suggest that DR-2 regulates expression of the Epo gene by acting as the binding site for different transcription factors in different types of cells.
Secretory phospholipase A2 predicts impending acute chest syndrome in sickle cell disease
Authors: Styles Lori A. , Aarsman Anton J. , Vichinsky Elliott P. , Kuypers Frans A.
Published: October 2019

Acute chest syndrome (ACS) is the leading cause of death in sickle cell disease. Severe ACS often develops in the course of a vaso-occlusive crisis (VOC), but currently there are no predictors for its development. Secretory phospholipase A2(sPLA2), a potent inflammatory mediator, is elevated in ACS, and previous work suggests that sPLA2 predicts impending ACS. We prospectively evaluated sPLA2concentration during 21 admissions for VOC; 6 of these patients went on to develop ACS. Elevation of sPLA2 was detected all 6 patients 24 to 48 hours before ACS was clinically diagnosed. Adding the requirement for fever raised the specificity of sPLA2 to 87% while retaining 100% sensitivity. These data indicate that sPLA2 can be useful in alerting the clinician to patients with impending ACS. In addition, sPLA2 may be useful for instituting early therapies to prevent or reduce the clinical morbidity of ACS.
Adhesion to 90K (Mac-2 BP) as a mechanism for lymphoma drug resistance in vivo
Authors: Fornarini Bruna , D'Ambrosio Consuelo , Natoli Clara , Tinari Nicola , Silingardi Vittorio , Iacobelli Stefano
Published: October 2019

A cell-adhesive protein of the human serum, 90K binds galactin-3, β1-integrins, collagens, and fibronectin, and it is of importance in cell-cell and cell–extracellular matrix adhesion. Serum 90K levels in 137 patients with lymphoma were measured by enzyme-linked immunosorbent assay. Compared with healthy controls, pretreatment serum 90K levels in patients with lymphoma were elevated (P < .001). Of 97 patients who showed objective response to treatment, 20 (21%) had pretreatment 90K levels above the normal cutoff compared with 17 (53%) of 32 patients who did not respond (P = .002). When used as a plastic-immobilized substrate, 90K caused a significant reduction in chemotherapy-induced apoptosis of Jurkat T lymphoma cells. This finding could explain the lack of response in lymphoma patients with high 90K serum levels.
Synergic effects of arsenic trioxide and cAMP during acute promyelocytic leukemia cell maturation subtends a novel signaling cross-talk
Authors: Zhu Qi , Zhang Ji-Wang , Zhu Hai-Qing , Shen Yu-Lei , Flexor Maria , Jia Pei-Ming , Yu Yun , Cai Xun , Waxman Samuel , Lanotte Michel , Chen Sai-Juan , Chen Zhu , Tong Jian-Hua
Published: October 2019

Acute promyelocytic leukemia (APL) is characterized by the specific chromosome translocation t(15;17) with promyelocytic leukemia-retinoic acid receptor-α (PML-RARA) fusion gene and the ability to undergo terminal differentiation as an effect of all-trans retinoic acid (ATRA). Recently, arsenic trioxide (As2O3) has been identified as an alternative therapy in patients with both ATRA-sensitive and ATRA-resistant APL. At the cellular level, As2O3 triggers apoptosis and a partial differentiation of APL cells in a dose-dependent manner; both effects are observed in vivo among patients with APL and APL animal models. To further explore the mechanism of As2O3-induced differentiation, the combined effects of arsenic and a number of other differentiation inducers on APL cell lines (NB4 and NB4-R1) and some fresh APL cells were examined. The data show that a strong synergy exists between a low concentration of As2O3 (0.25 μM) and the cyclic adenosine monophosphate (cAMP) analogue, 8-CPT-cAMP, in fully inducing differentiation of NB4, NB4-R1, and fresh APL cells. Furthermore, cAMP facilitated the degradation of As2O3-mediated fusion protein PML-RARα, a process considered to play a key role in overcoming the differentiation arrest of APL cells. On the other hand, cAMP could significantly inhibit cell growth by modulating several major players in G1/S transition regulation. Interestingly, H89, an antagonist of protein kinase A, could block the differentiation-inducing effect of As2O3potentiated by cAMP. These results thus support the existence of a novel signaling cross-talk for APL maturation, which may deepen understanding of As2O3-induced differentiation in vivo, and thus furnish insights for new therapeutic strategies.
Magnetic Field-Enhancing Photocatalytic Reaction in Micro Optofluidic Chip Reactor
Authors: Huang Hung Ji , Wang Yen Han , Chau Yuan-Fong Chou , Chiang Hai-Pang , Wu Jeffrey Chi-Sheng
Published: October 2019

A small external magnetic field (100–1000 Oe) was demonstrated to enhance the photocatalytic degradation of methyl orange (MO) using TiO2 NPs in micro optofluidic chip (MOFC) reactors. The rectangular shape of the fluidic channel and TiO2 deposited only onto the lower glass substrate leads to a selectively enhancing photocatalytic reactions by magnetic field in specific directions. Utilizing ethyl alcohol as a scavenger presented the difference between generated hot-hole (hVB+) and hot-electron (eCB−) pathways of photocatalytic reactions. Effects of dissolved oxygen (DO) and hydroxyl ions (OH−) are all demonstrated in a magnetic field-enhancing photocatalytic reaction. The experimental results demonstrate great potential for practical applications utilizing low-price fixed magnets in the field of green chemistry.
Intrinsic bubbles and Granger causality in the Hong Kong residential property market
Authors: Lan Ting
Published: October 2019

This study uses the intrinsic bubbles detection method to identify housing bubbles in the Hong Kong residential property market. By using sample period data from 1993 to 2019, the empirical results show evidence of intrinsic bubbles. Based on the unit root and co-integration tests, I found that there are no rational speculative bubbles in the Hong Kong residential property market. Furthermore, by using the Granger causality tests of the corresponding asymmetric VECM specification, there is no causality from lagged changes in the rental price returns to changes in the property price returns. However, there is strong evidence to show that changes in the property price index returns can Granger cause changes in the rental price index returns.
Response-based methods to measure road surface irregularity: a state-of-the-art review
Authors: Nguyen Teron , Lechner Bernhard , Wong Yiik Diew
Published: October 2019

Purpose

With the development of smart technologies, Internet of Things and inexpensive onboard sensors, many response-based methods to evaluate road surface conditions have emerged in the recent decade. Various techniques and systems have been developed to measure road profiles and detect road anomalies for multiple purposes such as expedient maintenance of pavements and adaptive control of vehicle dynamics to improve ride comfort and ride handling. A holistic review of studies into modern response-based techniques for road pavement applications is found to be lacking. Herein, the focus of this article is threefold: to provide an overview of the state-of-the-art response-based methods, to highlight key differences between methods and thereby to propose key focus areas for future research.

Methods

Available articles regarding response-based methods to measure road surface condition were collected mainly from “Scopus” database and partially from “Google Scholar”. The search period is limited to the recent 15 years. Among the 130 reviewed documents, 37% are for road profile reconstruction, 39% for pothole detection and the remaining 24% for roughness index estimation.

Results

The results show that machine-learning techniques/data-driven methods have been used intensively with promising results but the disadvantages on data dependence have limited its application in some instances as compared to analytical/data processing methods. Recent algorithms to reconstruct/estimate road profiles are based mainly on passive suspension and quarter-vehicle-model, utilise fewer key parameters, being independent on speed variation and less computation for real-time/online applications. On the other hand, algorithms for pothole detection and road roughness index estimation are increasingly focusing on GPS accuracy, data aggregation and crowdsourcing platform for large-scale application. However, a novel and comprehensive system that is comparable to existing International Roughness Index and conventional Pavement Management System is still lacking.
Robust structure measures of metabolic networks that predict prokaryotic optimal growth temperature
Authors: Weber Zendrera Adèle , Sokolovska Nataliya , Soula Hédi A.
Published: October 2019

Background

Metabolic networks reflect the relationships between metabolites (biomolecules) and the enzymes (proteins), and are of particular interest since they describe all chemical reactions of an organism. The metabolic networks are constructed from the genome sequence of an organism, and the graphs can be used to study fluxes through the reactions, or to relate the graph structure to environmental characteristics and phenotypes. About ten years ago, Takemoto et al. (2007) stated that the structure of prokaryotic metabolic networks represented as undirected graphs, is correlated to their living environment. Although metabolic networks are naturally directed graphs, they are still usually analysed as undirected graphs.

Results

We implemented a pipeline to reconstruct metabolic networks from genome data and confirmed some of the results of Takemoto et al. (2007) with today data using up-to-date databases. However, Takemoto et al. (2007) used only a fraction of all available enzymes from the genome and taking into account all the enzymes we fail to reproduce the main results. Therefore, we introduce three robust measures on directed representations of graphs, which lead to similar results regardless of the method of network reconstruction. We show that the size of the largest strongly connected component, the flow hierarchy and the Laplacian spectrum are strongly correlated to the environmental conditions.

Conclusions

We found a significant negative correlation between the size of the largest strongly connected component (a cycle) and the optimal growth temperature of the considered prokaryotes. This relationship holds true for the spectrum, high temperature being associated with lower eigenvalues. The hierarchy flow shows a negative correlation with optimal growth temperature. This suggests that the dynamical properties of the network are dependant on environmental factors.
EVR: reconstruction of bacterial chromosome 3D structure models using error-vector resultant algorithm
Authors: Hua Kang-Jian , Ma Bin-Guang
Published: October 2019

Background

More and more 3C/Hi-C experiments on prokaryotes have been published. However, most of the published modeling tools for chromosome 3D structures are targeting at eukaryotes. How to transform prokaryotic experimental chromosome interaction data into spatial structure models is an important task and in great need.

Results

We have developed a new reconstruction program for bacterial chromosome 3D structure models called EVR that exploits a simple Error-Vector Resultant (EVR) algorithm. This software tool is particularly optimized for the closed-loop structural features of prokaryotic chromosomes. The parallel implementation of the program can utilize the computing power of both multi-core CPUs and GPUs.

Conclusions

EVR can be used to reconstruct the bacterial 3D chromosome structure based on the contact frequency matrix derived from 3C/Hi-C experimental data quickly and precisely.
Protective role of berberine in isoprenaline-induced cardiac fibrosis in rats
Authors: Che Yan , Shen Di-Fei , Wang Zhao-Peng , Jin Ya-Ge , Wu Qing-Qing , Wang Sha-Sha , Yuan Yuan
Published: October 2019

Background

Cardiac fibrosis is a crucial aspect of cardiac remodeling that can severely affect cardiac function. Cardiac fibroblasts surely influence this process. Besides, macrophage plays an essential role in cardiac remodeling after heart injury. However, whether macrophage influence fibroblasts remain a question worth exploring. This study aimed to define the role of berberine (BBR) on isoprenaline (ISO)-induced cardiac fibrosis in an in vivo rat model and try to figure out the mechanism in vitro study.

Methods

The Sprague-Dawley rats were divided into five groups: control group, ISO-treated group, and ISO + BBR (10 mg/kg/d, 30 mg/kg/d, and 60 mg/kg/d orally)-pretreatment groups. Fibrosis was induced by ISO administration (5 mg/kg/d subcutaneously) for 10 days. One day after the last injection, all of the rats were sacrificed. Using picrosirius red (PSR) straining, immunohistochemistry, immunofluorescence, flow cytometry, western blot, RT-qPCR and cell co-culture, we explored the influence of pretreatment by BBR on ISO-induced cardiac fibrosis.

Results

Our results showed that BBR pretreatment greatly limited ISO-induced cardiac fibrosis and dysfunction. Moreover, BBR administration reduced macrophage infiltration into the myocardium of ISO-treated rats and inhibited transforming growth factor (TGF)-β1/smads signaling pathways in comparison to that seen in the ISO group. Besides, in vitro study showed that BBR-pretreatment reduced ISO-induced TGF-β1 mRNA expression in macrophages and ISO stimulation of macrophages significantly increased the expression of fibrotic markers in fibroblasts, but BBR-pretreatment blocked this increase.

Conclusion

Our results showed that BBR may have a protective role to cardiac injury via reducing of macrophage infiltration and forbidding fibroblasts transdifferent into an ‘activated’ secretory phenotype, myofibroblasts.
First insights into the genetic characteristics and drug resistance of Mycobacterium tuberculosis population collected during the first national tuberculosis prevalence survey of Lao PDR (2010–2011)
Authors: Somphavong Silaphet , Berland Jean-Luc , Gauthier Marie , Vu Thi Thuong , Nguyen Quang Huy , Iem Vibol , Vongvichit Phouvang , Inthavong Donekham , Akkhavong Vanthala , Chanthavilay Phetsavanh , Soundala Sengaloun , Keovichit Inthalaphone , Paranhos-Baccalà Glaucia , Paboriboune Phimpha , Nguyen Thi Van Anh , Bañuls Anne-Laure
Published: October 2019

Background

In Lao People’s Democratic Republic (PDR), tuberculosis (TB) prevalence was estimated at 540/100,000 in 2011. Nevertheless, little is known about the genetic characteristics and anti-TB drug resistance of the Mycobacterium tuberculosis population. The main objective of this work was to study the genetic characteristics and drug resistance of M. tuberculosis population collected during the first National TB Prevalence Survey (TBPS) of Lao PDR (2010–2011).

Methods

Two hundred and twenty two isolates collected during TBPS (2010–2011) were analyzed with the GenoType MTBDRplus test for M. tuberculosis identification and drug resistance detection. Then, 206 of the 222 isolates were characterized by spoligotyping and MIRU-VNTR typing.

Results

Among the 222 M. tuberculosis isolates, 11 were mono-resistant to isoniazid and 2 were resistant to isoniazid and rifampicin (MDR-TB), using the GenoType MTBDRplus test. Among the 202 genetically characterized isolates, the East African-Indian (EAI) family was predominant (76.7%) followed by the Beijing (14.4%) and T (5.5%) families. EAI isolates came from all the country provinces, whereas Beijing isolates were found mainly in the northern and central provinces. A higher proportion of Beijing isolates was observed in people younger than 35 years compared to EAI. Moreover, the percentage of drug resistance was higher among Beijing (17.2%) than EAI (5.2%) isolates, and the two MDR-TB isolates belonged to the Beijing family. Combined analysis of the MIRU-VNTR and spoligotyping results (n = 202 isolates) revealed an estimated clustering rate of 11% and the occurrence of mini-outbreaks of drug-resistant TB caused by Beijing genotypes.

Conclusions

The EAI family, the ancient and endemic family in Asia, is predominant in Lao PDR whereas the prevalence of Beijing, the most harmful M. tuberculosis family for humans, is still low, differently from neighboring countries. However, its association with drug resistance, its presence in young patients and its potential association with recent transmission suggest that the Beijing family could change TB epidemiological pattern in Lao PDR. Therefore, efficient TB control and surveillance systems must be maintained and reinforced to prevent the emergence of highly transmissible and drug-resistant strains in Lao PDR, as observed in neighboring countries.
CD40 polymorphisms were associated with HCV infection susceptibility among Chinese population
Authors: Tian Ting , Huang Peng , Wu Jingjing , Wang Chunhui , Fan Haozhi , Zhang Yun , Yu Rongbin , Wu Chao , Xia Xueshan , Fu Zuqiang , Li Jun , Yue Ming
Published: October 2019

Background

CD40, encoded byTNFRSF5, participates in the survival of B cells, process of antigen presentation and generation of CD8+ T cell memory. It also has an important effect on HCV antiviral immune response. This study aims to investigate whetherTNFRSF5gene polymorphisms are associated with HCV infection outcomes among Chinese population.

Methods

Three single nucleotide polymorphism (SNPs) (rs1535045, rs1883832, rs4810485) onTNFRSF5were genotyped by TaqMan assay among Chinese population, including 1513 uninfected subjects, 496 spontaneous viral clearance subjects and 768 persistent HCV-infected subjects. Logistic analysis was used to compare these SNPs among different groups in this cross-sectional study. Functional annotations of the identified SNPs were further evaluated by bioinformatics analysis.

Results

After adjusted by age, gender and routes of infection, the results of logistic analysis indicated that individuals carrying rs1535045 T allele had a higher risk to infect HCV compared with C allele (in recessive model, adjusted OR = 1.368, 95%CI = 1.070-1.749,P = 0.012). Subjects carried rs1535045 TT genotype were more likely to infect HCV than wild CC genotype (adjusted OR = 1.397, 95%CI = 1.078-1.809,P = 0.011). For rs1883832, T allele was significantly associated with an increased risk of HCV infection (in recessive model, adjusted OR = 1.337, 95%CI = 1.069-1.673,P = 0.011). Subjects with TT genotype had more possibility to infect HCV (adjusted OR = 1.351, 95%CI = 1.060-1.702,P = 0.015). In the stratified analysis, rs1535045 and rs1883832 were remained in various subgroups and the heterogeneity test showed no pronounced heterogeneity in any pairwise comparison (allP > 0.05). In addition, the results of the cumulative effects showed a tendency of that the more risk alleles (rs1535045 T and rs1883832 T) subjects carried, the more possibility of HCV infection exhibited (P<0.001). In haplotype analyses, compared with the CC haplotype, CT, TC and TT was correlated with an increased risk to infect HCV (P = 0.029,P = 0.047 andP<0.001, respectively).

Conclusions

In conclusion,CD40polymorphisms were significantly associated with the susceptibility to HCV among Chinese populations.
An outbreak of Salmonella Saintpaul in a Scottish childcare facility: the influence of parental under-reporting
Authors: Thomson Rachel M. , Henderson Hazel J. , Smith-Palmer Alison
Published: October 2019

Background

Salmonellaoutbreaks in childcare facilities are relatively rare, most often occurring secondary to contaminated food products or poor infection control practices. We report an outbreak ofSalmonellaSaintpaul at a pre-school facility in Ayrshire, Scotland with atypical clinical and epidemiological features.

Methods

Following notification of the initial two cases, the multi-disciplinary Incident Management Team initiated enhanced active case finding and two environmental inspections of the site, including food preparation areas. Parent and staff interviews were conducted by the Public Health department covering attendance, symptomatology and risk factors for all probable and confirmed cases. Microbiological testing of stool samples and the facility water tank was conducted. Whole Genome Sequencing (WGS) was performed for positive stool samples at the national reference laboratory. Infection control measures were introduced iteratively due to the atypical progression of the outbreak.

Results

There were 15 confirmed cases and 3 children admitted to hospital during the outbreak. However, 35.7% of cases reported extremely mild symptoms. The attack rate was 15.2%, and age of affected children ranged from 18 to 58 months (mean 35 months). All cases were the same Multilocus Sequence Type (MLST50). Epidemiological investigation strongly suggested person-to-person spread within the facility. Existing infection control practices were found to be of a high standard, but introduction of additional evidence-based control measures was inadequate in halting transmission. Facility staff reported concerns about lack of parental disclosure of gastrointestinal symptoms, particularly where these were mild, with 50.0% of cases having attended while symptomatic against public health advice. Voluntary two-week closure of the facility was implemented to halt transmission, following which there were no new cases. WGS results were unavailable until after the decision was taken to close the facility.

Conclusions

This is the first reported instance of aSalmonellaSaintpaul outbreak at a childcare facility, or where person-to-person transmission is indicated. Clinicians should consider the influence of parental under-reporting on gastrointestinal outbreaks in childcare settings, particularly where perceived severity is low and financial or social pressures to attend work may reduce compliance. WGS cannot yet replace conventional microbiological techniques during short, localised outbreaks due to delays receiving results.
Using electronic medication monitoring to guide differential management of tuberculosis patients at the community level in China
Authors: Wang Ni , Zhang Hui , Zhou Yang , Jiang Hui , Dai Bing , Sun Miaomiao , Li Ying , Kinter Amelia , Huang Fei
Published: October 2019

Background

In settings such as China, where universal implementation of directly observed therapy (DOT) is not feasible, innovative approaches are needed to support patient adherence to TB treatment. The electronic medication monitor (EMM) is one of the digital technologies recommended by the World Health Organization (WHO), but evidence from implementation studies remains sparse. In this study, we evaluated acceptance of the EMM among health care workers and patients while implementing the device for differential TB patient management at the community level.

Methods

Zhenjiang City in Jiangsu Province was purposively selected for the study. All participating patients were allowed to select their preferred management approach. If patients declined to use the EMM, DOT was offered. The EMM was designed to hold 1 month of anti-TB drugs for once-daily dosing of fixed-dose combination (FDC) tablets. Patient EMM records were monitored monthly by a physician; if 20 to 50% of doses were missed twice, or more than 50% of doses were missed once, the patient was switched to DOT. The four physicians and five nurses involved in the study at four designated hospitals were surveyed using a structured questionnaire to assess their acceptance of the EMM.

Results

From October 2017 through January 2018, 316 pulmonary TB patients were notified in the TB information management system, and 231 (73.1%) met the study enrollment criteria. Although 186 patients (80.5%) initially consented to use the EMM, 17 later refused to use it. Among the 169 patients who used the EMM, 15 (8.9%) were switched to DOT due to poor adherence, and the other 154 completed the treatment course. The median adherence rate was 99.3%. Surveyed health care workers from designated hospitals found the EMM acceptable, although eight of nine felt use of the device moderately increased their workload. However, the EMM program significantly reduced the workload of community physicians by reducing patient visits by 87.9%.

Conclusions

This study demonstrated the acceptability of using an indigenously developed EMM for differential management of TB patients at the community level. However, more operational research should be conducted before introducing and scaling the technology throughout China.
Geographic distribution and risk of upper urothelial carcinomas in Croatia, 2001–2011
Authors: Medunjanin Danira , Sonicki Zdenko , Vena John E. , Cvitkovic Ante , Robb Sara Wagner
Published: October 2019

Background

Strong associations exist between Balkan endemic nephropathy (BEN) and upper urothelial carcinomas (UUCs). However, the common etiology between the two remains unclear and there are no studies to date that visualize UUC risks in Croatia. In Croatia, 14 villages in the southwestern part of Brod-Posavina County are considered endemic for BEN. The aim of this ecological study is to map cancer risks and describe the case distribution of UUCs in Croatia at the county level during 2001–2011.

Methods

A total of 608 incident cases from the Croatian National Cancer Registry were identified. Indirect standardization was employed to compute standardized incidence ratios (SIRs).

Results

Counties with SIRs greater than 1 were concentrated around the agricultural region of Slavonia and the coastal region of Dalmatia. However, only Brod-Posavina County and Vukovar-Srijem County had a statistically significant risk of UUC development, where there were 390 and 210% more UUC cases observed than expected, respectively. Only unique to Brod-Posavina County, females were at higher risk (SIR 4.96; 95% CI 3.59–6.34) of developing UUCs than males (SIR 3.03; 95% CI 2.04–4.01) when compared to their Croatian counterparts. Although Brod-Posavina County only made up 3.7% of the total Croatian population (as of 2011), it had the highest frequency of incident UUC cases after the capital City of Zagreb. No elevated cancer risks were noted in the City of Zagreb, even after stratifying by sex.

Conclusion

Our findings suggest that Brod-Posavina County had the highest cancer risk for UUCs, especially among females, when compared to Croatia as a whole during 2001–2011. Given that a majority of BEN patients develop associated UUCs, concurrent screening programs for UUCs and BEN should be considered not only in endemic areas of BEN but also the surrounding rural areas and amongst at-risk groups such as those undergoing hemodialysis, who frequently develop UUCs, to help clarify BEN-UUC associations by identifying common risk factors while standardizing disease estimates across endemic regions for BEN.
CSB affected on the sensitivity of lung cancer cells to platinum-based drugs through the global decrease of let-7 and miR-29
Authors: Yang Zhenbang , Liu Chunling , Wu Hongjiao , Xie Yuning , Gao Hui , Zhang Xuemei
Published: October 2019

Background

Transcription-coupled nucleotide excision repair (TC-NER) plays a prominent role in the removal of DNA adducts induced by platinum-based chemotherapy reagents. Cockayne syndrome protein B (CSB), the master sensor of TCR, is also involved in the platinum resistant. Let-7 and miR-29 binding sites are highly conserved in the proximal 3′UTR of CSB.

Methods

We conducted immunohistochemisty to examine the expression of CSB in NSCLC. To determine whether let-7 family and miR-29 family directly interact with the putative target sites in the 3′UTR of CSB, we used luciferase reporter gene analysis. To detect the sensitivity of non-small cell lung cancer (NSCLC) cells to platinum-based drugs, CCK analysis and apoptosis analysis were performed.

Results

We found that let-7 and miR-29 negatively regulate the expression of CSB by directly targeting to the 3′UTR of CSB. The endogenous CSB expression could be suppressed by let-7 and miR-29 in lung cancer cells. The suppression of CSB activity by endogenous let-7 and miR-29 can be robustly reversed by their sponges. Down-regulation of CSB induced apoptosis and increased the sensitivity of NSCLC cells to cisplatin and carboplatin drugs. Let-7 and miR-29 directly effect on cisplatin and carboplatin sensitivity in NSCLC.

Conclusions

In conclusion, the platinum-based drug resistant of lung cancer cells may involve in the regulation of let-7 and miR-29 to CSB.
Factors affecting the growth of infants diagnosed with cystic fibrosis by newborn screening
Authors: Patterson K. D. , Kyriacou T. , Desai M. , Carroll W. D. , Gilchrist F. J.
Published: October 2019

Background

Newborn screening (NBS) for cystic fibrosis (CF) improves nutritional outcomes. Despite early dietetic intervention some children fail to grow optimally. We report growth from birth to 2 years in a cohort of children diagnosed with CF by NBS and identify the variables that influence future growth.

Methods

One hundred forty-four children were diagnosed with CF by the West Midlands Regional NBS laboratory between November 2007 and October 2014. All anthropometric measurements and microbiology results from the first 2 years were collated as was demographic and CF screening data. Classification modelling was used to identify the key variables in determining future growth.

Results

Complete data were available on 129 children. 113 (88%) were pancreatic insufficient (PI) and 16 (12%) pancreatic sufficient (PS). Mean birth weight (z score) was 3.17 kg (− 0.32). There was no significant difference in birth weight (z score) between PI and PS babies: 3.15 kg (− 0.36) vs 3.28 kg (− 0.05); p = 0.33. By the first clinic visit the difference was significant: 3.42 kg (− 1.39) vs 4.60 kg (− 0.48); p < 0.0001. Weight and height remained lower in PI infants in the first year of life. In the first 2 years of life, 18 (14%) infants failed to regain their birth weight z score. The median time to achieve a weight z score of − 2, − 1 and 0 was 18, 33 and 65 weeks respectively. The median times to reach the same z scores for height were 30, 51 and 90 weeks. Birth weight z score, change in weight z score from birth to first clinic, faecal elastase, isolation of Pseudomonas aeruginosa, isolation of Staphylococcus aureus and sweat chloride were the variables identified by the classification models to predict weight and height in the first and second year of life.

Conclusions

Babies with CF have a lower birth weight than the healthy population. For those diagnosed with CF by NBS, the weight difference between PI and PS babies was not significantly different at birth but became so by the first clinic visit. The presence of certain factors, most already identifiable at the first clinic visit can be used to identify infant at increased risk of poor growth.