Nanocrystalline TiO2 doped by small amount of pre-synthesized colloidal CdS nanoparticles for photocatalytic degradation of 1,2,4-trichlorobenzene

The chemical stability and hydrophobic nature of chloroarenes make them a persistent environmental hazard. Modeling of 1,2,4-trichlorobenzene (1,2,4-TCB) degradation in alcohol-water solution under UV irradiation was carried out with the aim of probing how the 1,2,4-TCB might behave in the environment. The photocatalytic activity of both bare TiO₂ and TiO₂ doped by colloidal CdS nanoparticles synthesized by the sol-gel method has been investigated in the processes of 1,2,4-TCB photodegradation in the aqueous protic solvent. Non-sensitized TiO₂ cannot be regarded as catalyst for the 1,2,4-TCB photodecomposition. On the contrary, the CdS/TiO₂ composite accelerated the 1,2,4-TCB photodegradation process. The concentration of CdS/TiO₂ was shown to effect on the 1,2,4-TCB photolysis mechanisms, which resulted in the quantitative ratios of the 1,2,4-TCB photolysis products.     

Sense-antisense gene-pairs in breast cancer and associated pathological pathways

More than 30% of human protein-coding genes form hereditary complex genome architectures composed of sense-antisense (SA) gene pairs (SAGPs) transcribing their RNAs from both strands of a given locus. Such architectures represent important novel components of genome complexity contributing to gene expression deregulation in cancer cells. Therefore, the architectures might be involved in cancer pathways and, in turn, be used for novel drug targets discovery. However, the global roles of SAGPs in cancer pathways has not been studied. Here we investigated SAGPs associated with breast cancer (BC)-related pathways using systems biology, prognostic survival and experimental methods. Gene expression analysis identified 73 BC-relevant SAGPs that are highly correlated in BC. Survival modelling and metadata analysis of the 1161 BC patients allowed us to develop a novel patient prognostic grouping method selecting the 12 survival-significant SAGPs. The qRT-PCR-validated 12-SAGP prognostic signature reproducibly stratified BC patients into low- and high-risk prognostic subgroups. The 1381 SAGP-defined differentially expressed genes common across three studied cohorts were identified. The functional enrichment analysis of these genes revealed the GABPA gene network, including BC-relevant SAGPs, specific gene sets involved in cell cycle, spliceosomal and proteasomal pathways. The co-regulatory function of GABPA in BC cells was supported using siRNA knockdown studies. Thus, we demonstrated SAGPs as the synergistically functional genome architectures interconnected with cancer-related pathways and associated with BC patient clinical outcomes. Taken together, SAGPs represent an important component of genome complexity which can be used to identify novel aspects of coordinated pathological gene networks in cancers.     

Exceptionally strong easterly wind burst stalling El Ni?o of 2014

Intraseasonal wind bursts in the tropical Pacific are believed to affect the evolution and diversity of El Niño events. In particular, the occurrence of two strong westerly wind bursts (WWBs) in early 2014 apparently pushed the ocean–atmosphere system toward a moderate to strong El Niño—potentially an extreme event according to some climate models. However, the event’s progression quickly stalled, and the warming remained very weak throughout the year. Here, we find that the occurrence of an unusually strong basin-wide easterly wind burst (EWB) in June was a key factor that impeded the El Niño development. It was shortly after this EWB that all major Niño indices fell rapidly to near-normal values; a modest growth resumed only later in the year. The easterly burst and the weakness of subsequent WWBs resulted in the persistence of two separate warming centers in the central and eastern equatorial Pacific, suppressing the positive Bjerknes feedback critical for El Niño. Experiments with a climate model with superimposed wind bursts support these conclusions, pointing to inherent limits in El Niño predictability. Furthermore, we show that the spatial structure of the easterly burst matches that of the observed decadal trend in wind stress in the tropical Pacific, suggesting potential links between intraseasonal wind bursts and decadal climate variations.El Niño, the warm phase of the El Niño–Southern Oscillation (ENSO), is characterized by anomalously warm water appearing in the central and eastern equatorial Pacific every 2–7 years, driven by tropical ocean–atmosphere interactions with far-reaching global impacts (recent reviews are in refs. 1–3). These interactions and El Niño development involve several important feedbacks, including the positive Bjerknes feedback [zonal wind relaxation leads to the reduction of the zonal sea surface temperature (SST) gradient and further wind relaxation] (4). Since the year 2000, there has been a shift in the observed properties of El Niño, including its magnitude, frequency, and spatial structure of temperature anomalies (5, 6). For example, El Niño events occurred more frequently than during the previous two decades, but all were weak, and none reached the extreme magnitude of the 1982 and 1997 events. Concurrently, the rise of global mean surface temperature has slowed down with the so-called global warming hiatus (7–9). The stalled development of the 2014 El Niño presents a showcase to explore the relevant connection and mechanisms of these changes.At the beginning of 2014, many in the scientific community anticipated that a moderate to strong El Niño could develop by the end of the year (10–14) (Fig. S1). In March, the National Oceanic and Atmospheric Administration (NOAA) Climate Prediction Center announced an “El Niño watch” based on predictions made by dynamical and statistical models (12), attracting attention of the general public. Admittedly, these predictions encompassed large uncertainties because of the stochastic nature of the tropical climate system (15–17). In May, the National Aeronautics and Space Administration (NASA) suggested that 2014 could potentially rival the strongest on-record event of 1997/19998 (Fig. 1B), while acknowledging the large existing uncertainty (14); their projection was supported by satellite observations of strong Kelvin waves evident in sea surface height (SSH) (Fig. 2C). The spread of spring forecast plumes from some climate models, for example that of the European Centre for Medium-Range Weather Forecasts (ECMWF), included the possibility of a failed El Niño (Fig. S1) but only as a low-probability outcome involving unusual instances of weather noise. The observed development fell near the limit of these forecast possibilities after June and July, and eventually, the 2014 warm event barely qualified as El Niño (Fig. 1A).Open in a separate windowFig. 1.El Niño development in (A and C) 2014 and (B and D) 1997. (A and B) Evolution of the Niño3, Niño4, and Niño3.4 indices; the first two indices describe SST anomalies (in degrees Celsius) in the eastern and central equatorial Pacific, respectively, whereas the last index covers the region in between. (C and D) Variation in the zonal wind stress indices. These indices are obtained by averaging wind stress anomalies (in 10⁻² newtons per meter²) in the equatorial Pacific zonally and between 5 °S and 5 °N and then selecting negative (blue; easterly anomalies), positive (red; westerly anomalies), or full values (black) (Materials and Methods). The spatial averaging is intended to take into account both the magnitude and the fetch of the wind bursts. During 2014, two early year WWBs were followed by an exceptional EWB in June (highlighted by pink and blue, respectively). This easterly burst apparently led to a rapid decrease of the Niño indices (A). In contrast, the 1997 El Niño exhibited persistent westerly wind activity throughout the year. The graphs start on January 1.Open in a separate windowFig. 2.Spatiotemporal evolution of the 2014 El Niño. (A–D) Hovmöller diagrams for anomalies in (A) SST, (B) zonal wind stress, (C) SSH, and (D) surface zonal currents in the equatorial Pacific. Time goes downward. The SSH and surface velocity plots highlight the eastward propagating downwelling Kelvin waves, especially pronounced early in the year, and a strong upwelling Kelvin wave midyear. (E and F) El Niño development in 2014 (black line) compared with several historical (E) EP and (F) CP events. The diagrams show the position of the Warm Pool Eastern Edge (degrees of longitude) vs. the Niño3 SST (degrees Celsius) for different months of the year. The Warm Pool Eastern Edge is defined as the position of the 29 °C isotherm at the equator. Numbers indicate monthly averages (1, January; 2, February, etc.). The light vertical line marks the Dateline. In 2014, both the warm pool displacement and Niño3 SST anomalies were exceptionally large during May (month 5), were similar to those in 1997 and 1982 (the strongest events of the 20th century), and then, rapidly decreased by August (month 8).Open in a separate windowFig. S1.The El Niño spring forecasts of the Niño3.4 index from the European Centre for Medium-Range Weather Forecasts (ECMWF). Red lines show 50 ensemble members of the forecast plume initiated in March of 2014; the black dotted line indicates the observed Niño3.4 index. The observed development fell outside the forecast plume in June and July and remained beyond the typical forecast spread after that. Adapted from ref. 13.The question then arises as to which dynamic factors controlled the temporal and spatial development in the tropical Pacific in 2014. This warm event began with a rapid growth, such that, in early June, all major Niño indices (Materials and Methods) along the equator were nearly identical to those during the same time of 1997 (Fig. 1 A and B). A substantial warming also developed along the Peruvian coast (Fig. 3A). Then, the event’s progression slowed down or even reversed. By year end, the equatorial warming barely exceeded 1 °C, but the SST anomaly stretched uncharacteristically across the entire equatorial Pacific almost uniformly (Figs. 1A and ​and2A).2A). Accordingly, the major goal of this study is to investigate this unusual development, identify the main factors that impeded this event, and explore its broad implications.Open in a separate windowFig. 3.The June of 2014 EWB in satellite-based data. (A) The spatial structure of anomalies in surface winds (vectors; in meters per second) and SST (colors; in degrees Celsius) on June 12, 2014, when the burst was strongest. (B) Daily vs. weekly mean values of the zonal wind stress index (10⁻² newtons per meter²) for the period 1988–2014. The blue cross marks the peak value of the June of 2014 EWB. The wind stress index is defined as anomalous zonal wind stress averaged in the equatorial Pacific zonally and between 5 °S and 5 °N (Materials and Methods). Black circles are for the year 2014, red circles are for all El Niño years before 2014, and gray circles are for all other years (La Niña or neutral). Note that the June of 2014 EWB appears strongest in the satellite record for not only daily data but also, weekly averaged values, which confirms that the observations are robust.     

The phosphorylation state of Ser-129 in human alpha-synuclein determines neurodegeneration in a rat model of Parkinson disease

Studies have shown that alpha-synuclein (alpha-syn) deposited in Lewy bodies in brain tissue from patients with Parkinson disease (PD) is extensively phosphorylated at Ser-129. We used recombinant Adeno-associated virus (rAAV) to overexpress human wild-type (wt) alpha-syn and two human alpha-syn mutants with site-directed replacement of Ser-129 to alanine (S129A) or to aspartate (S129D) in the nigrostriatal tract of the rat to investigate the effect of Ser-129 phosphorylation state on dopaminergic neuron pathology. Rats were injected with rAAV2/5 vectors in the substantia nigra pars compacta (SNc) on one side of the brain; the other side remained as a nontransduced control. The level of human wt or mutant alpha-syn expressed on the injected side was about four times the endogenous rat alpha-syn. There was a significant reduction of dopaminergic neurons in the SNc and dopamine (DA) and tyrosine hydroxylase (TH) levels in the striatum of all S129A-treated rats as early as 4 wk postinjection. Nigral DA pathology occurred more slowly in the wt-injected animals, but by 26 wk the wt alpha-syn group lost nigral TH neurons equivalent to the mutated S129A group at 8 wk. In stark contrast, we did not observe any pathological changes in S129D-treated animals. Therefore, the nonphosphorylated form of S129 exacerbates alpha-syn-induced nigral pathology, whereas Ser-129 phosphorylation eliminates alpha-syn-induced nigrostriatal degeneration. This suggests possible new therapeutic targets for Parkinson Disease.     

High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis

High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (auto-HSCT) is a new and promising approach to the treatment of multiple sclerosis (MS) patients because currently there are no effective treatment methods for this disease. In this article, we present results of a prospective clinical study of efficacy of HDIT + auto-HSCT in MS patients. The following treatment strategies were employed in the study: "early," "conventional," and "salvage/late" transplantation. Fifty patients with various types of MS were included in this study. No toxic deaths were reported among 50 MS patients; transplantation procedure was well-tolerated by the patients. The efficacy analysis was performed in 45 patients. Twenty-eight patients achieved an objective improvement of neurological symptoms, defined as at least 0.5-point decrease in the Expanded Disability Status Scale (EDSS) score as compared to the baseline and confirmed during 6 months, and 17 patients had disease stabilization (steady EDSS level as compared to the baseline and confirmed during 6 months). The progression-free survival at 6 years after HDIT + auto-HSCT was 72%. Magnetic resonance imaging data were available in 37 patients before transplantation showing disease activity in 43.3%. No active, new, or enlarging lesions were registered in patients without disease progression. In conclusion, HDIT + auto-HSCT suggests positive results in management of patients with different types of MS. Identification of treatment strategies based on the level of disability, namely "early," "conventional," and "salvage/late" transplantation, appears to be feasible to improve treatment outcomes.     

A novel IVS2 -2A>T splicing mutation in the GH-1 gene in familial isolated growth hormone deficiency type II in the spectrum of other splicing mutations in the Russian population

Isolated GH deficiency (IGHD) is characterized by genetic heterogeneity, both in familial and sporadic cases. To determine if this statement can be applied to the Russian population, we performed screening for mutations in the GH-1 gene in children living in Russia with IGHD. Twenty-eight children from 26 families with total IGHD were studied. DNA fragments, covering each of four (2-5) exons of GH-1 were amplified using PCR. Single-strand conformation polymorphism analysis followed by direct DNA sequencing identified five heterozygous mutations of splicing in intron 2, intron 3, and exon 4 of GH-1; three of them were not previously reported. We concentrated here on dominant-negative mutations causing IGHD type II, which were as follows: 1) A>T transversion of the second base of the 3'-acceptor splice site of intron 2 (IVS2 -2A>T); 2) T>C transition of the second base of the 5'-donor splice site of intron 3 (IVS3 +2T>C); 3) G>A transition of the first base of the 5'-donor splice site of intron 3 (IVS3 +1G>A). Our data indicate allelic heterogeneity of IGHD type II (IGHD II). However, all mutations in Russian IGHD II patients affect splicing, a striking difference from the mutation spectrum of other IGHD forms. The IVS2 -2A>T mutation is the first identified mutation in intron 2 of GH-1. The 5'-donor splice site of intron 3 of GH-1 is a mutational hot spot, and the IVS3 +1G>A mutation can be considered to be a common molecular defect in IGHD II in Russian patients.     

Detection and phasing of single base de novo mutations in biopsies from human in vitro fertilized embryos by advanced whole-genome sequencing

Currently, the methods available for preimplantation genetic diagnosis (PGD) of in vitro fertilized (IVF) embryos do not detect de novo single-nucleotide and short indel mutations, which have been shown to cause a large fraction of genetic diseases. Detection of all these types of mutations requires whole-genome sequencing (WGS). In this study, advanced massively parallel WGS was performed on three 5- to 10-cell biopsies from two blastocyst-stage embryos. Both parents and paternal grandparents were also analyzed to allow for accurate measurements of false-positive and false-negative error rates. Overall, >95% of each genome was called. In the embryos, experimentally derived haplotypes and barcoded read data were used to detect and phase up to 82% of de novo single base mutations with a false-positive rate of about one error per Gb, resulting in fewer than 10 such errors per embryo. This represents a ∼100-fold lower error rate than previously published from 10 cells, and it is the first demonstration that advanced WGS can be used to accurately identify these de novo mutations in spite of the thousands of false-positive errors introduced by the extensive DNA amplification required for deep sequencing. Using haplotype information, we also demonstrate how small de novo deletions could be detected. These results suggest that phased WGS using barcoded DNA could be used in the future as part of the PGD process to maximize comprehensiveness in detecting disease-causing mutations and to reduce the incidence of genetic diseases.Worldwide, more than 5 million babies (Ferraretti et al. 2013) have been born through in vitro fertilization (IVF) since the birth of the first in 1978 (Steptoe and Edwards 1978). Exact numbers are difficult to determine, but it has been estimated that currently 350,000 babies are born yearly through IVF (de Mouzon et al. 2009, 2012; Centers for Disease Control and Prevention 2011; Ferraretti et al. 2013). That number is expected to rise, as advanced maternal age is associated with decreased fertility rates and women in developed countries continue to delay childbirth to later ages. In 95% of IVF procedures, no diagnostic testing of the embryos is performed (https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0). Couples with prior difficulties conceiving or those wishing to avoid the transmission of highly penetrant heritable diseases often choose to perform preimplantation genetic diagnosis (PGD). PGD involves the biopsy of one cell from a 3-d embryo or the recently more preferred method, due to improved implantation success rates (Scott et al. 2013b), of up to 10 cells from a 5- to 6-d blastocyst-stage embryo. Following biopsy, genetic analysis is performed on the isolated cell(s). Currently this is an assay for translocations and the correct chromosome copy number (Hodes-Wertz et al. 2012; Munne 2012; Yang et al. 2012; Scott et al. 2013a; Yin et al. 2013), a unique test designed and validated for each specific heritable disease (Gutierrez-Mateo et al. 2009), or a combination of both (Treff et al. 2013). Importantly, none of these approaches can detect de novo mutations.Advanced maternal age has long been associated with an increased risk of producing aneuploid embryos (Munne et al. 1995; Crow 2000; Hassold and Hunt 2009) and giving birth to a child afflicted with Down syndrome or other diseases resulting from chromosomal copy number alterations. Conversely, children of older fathers have been shown to have an increase in single base and short multibase insertion/deletion (indels) de novo mutations (Kong et al. 2012). Many recent large-scale sequencing studies have found that de novo variations spread across many different genes are likely to be the cause of a large fraction of autism cases (Michaelson et al. 2012; O’Roak et al. 2012; Sanders et al. 2012; De Rubeis et al. 2014; Iossifov et al. 2014), severe intellectual disability (Gilissen et al. 2014), epileptic encephalopathies (Epi4K Consortium and Epilepsy Phenome/Genome Project 2013), and many other congenital disorders (de Ligt et al. 2012; Veltman and Brunner 2012; Yang et al. 2013; Al Turki et al. 2014). Additionally rare and de novo variations have been suggested to be prevalent in patients with schizophrenia (Fromer et al. 2014; Purcell et al. 2014), and Michaelson et al. (2012) found that single base de novo mutations affect conserved regions of the genome and essential genes more often than regions of unknown function. Current targeted approaches to PGD would miss many of these important functional changes within the embryonic DNA sequence, and even a whole-genome sequencing (WGS)–based carrier screen of both parents would not enable comprehensive preimplantation or prenatal diagnoses due to de novo mutations. As more parents delay childbirth into their mid-30s and later, these studies suggest we should try to provide better diagnostic tests for improving the health of newborns. In this study, we demonstrate the use of an advanced WGS process that provides an accurate and phased genome sequence from about 10 cells, allowing highly sensitive and specific detection of single base de novo mutations from IVF blastocyst biopsies.     

The length‐dependent activation of contraction is equally impaired in impuberal male and female rats in monocrotaline‐induced right ventricular failure

The length‐dependent activation of contraction is attenuated in the failing myocardium of adult male rats. This pathological change is not seen in adult female rats, possibly because of a protective effect of sex hormones. The present study evaluated length‐dependent changes in isometric twitch, Ca²⁺ transient (CaT) and action potential (AP) in the right ventricular myocardium of impuberal healthy male and female rats (control) and in rats treated with a single injection of 50 mg/kg monocrotaline (MCT). Compared with sex‐matched control rats, MCT‐treated male and female rats exhibited increased right ventricular weight (134% and 142% of control, respectively), decreased left ventricular weight (72% and 79%), twitch attenuation (48.8 ± 2.7% and 57.5 ± 1.2%) and prolongation (125 ± 3% and 127 ± 2%), CaT attenuation (37.8 ± 0.4% and 39.1 ± 1.1%) and prolongation (114 ± 1% and 116 ± 1%) and AP prolongation at 90% repolarization (195 ± 2% and 203 ± 1%). The MCT‐treated male rats exhibited a 50% lower integral magnitude and an approximately 25% larger time‐to‐peak ‘bump’ compared with control male rats. These parameters in MCT‐treated female rats tended to show similar changes to those seen in the control female rats, with no significant difference between the two groups. In all groups, integral magnitude and time‐to‐peak ‘bump’ increased with length. In conclusion, the length‐dependent activation of contraction was equally blunted in the failing right ventricular myocardium of impuberal male and female rats. This was related to changes in CaT and AP, which were similar between male and female rats. Therefore, puberty is necessary for manifestation of the protective effects of sex hormones on this remodelling.     

Adenosine receptors in regulation of dendritic cell differentiation and function

Differentiation of functional dendritic cells (DCs) critically depends on the microenvironment. DCs differentiate in hypoxic tumor sites and inflamed or damaged tissue. Because local concentrations of adenosine reach high physiologically relevant levels in these conditions, we assessed the expression of adenosine receptors and the effect of their activation on differentiation of human monocytes and mouse peritoneal macrophages and hematopoietic progenitor cells (HPCs) into myeloid DCs. Stimulation of adenosine receptors skews DC differentiation toward a distinct cell population characterized by expression of both DC and monocyte/macrophage cell surface markers. Pharmacologic analysis and experiments with cells from A(2B) adenosine receptor knockout mice identified A(2B) receptor as the mediator of adenosine effects on DCs. Unlike normal myeloid DCs, adenosine-differentiated DCs have impaired allostimulatory activity and express high levels of angiogenic, pro-inflammatory, immune suppressor, and tolerogenic factors, including VEGF, IL-8, IL-6, IL-10, COX-2, TGF-beta, and IDO. They promoted tumor growth if injected into tumors implanted in mice. Using adenosine desaminase knockout animals, we showed that DCs with proangiogenic phenotype are highly abundant under conditions associated with elevated levels of extracellular adenosine in vivo. Adenosine signaling through A(2B) receptor is an important factor of aberrant DC differentiation and generation of tolerogenic, angiogenic, and proinflammatory cells.