Although it is known that molecular interactions govern morphology formation and purity of mixed domains of conjugated polymer donors and small-molecule acceptors, and thus largely control the ...achievable performance of organic solar cells, quantifying interaction-function relations has remained elusive. Here, we first determine the temperature-dependent effective amorphous-amorphous interaction parameter, χ
(T), by mapping out the phase diagram of a model amorphous polymer:fullerene material system. We then establish a quantitative 'constant-kink-saturation' relation between χ
and the fill factor in organic solar cells that is verified in detail in a model system and delineated across numerous high- and low-performing materials systems, including fullerene and non-fullerene acceptors. Our experimental and computational data reveal that a high fill factor is obtained only when χ
is large enough to lead to strong phase separation. Our work outlines a basis for using various miscibility tests and future simulation methods that will significantly reduce or eliminate trial-and-error approaches to material synthesis and device fabrication of functional semiconducting blends and organic blends in general.
A careful prognostic evaluation of patients referred for high-dose therapy (HDT) is warranted to identify those who maximally benefit from HDT as well as those who clearly fail current HDT and are ...candidates for more innovative treatments. In a series of 110 patients with myeloma who received HDT as first-line therapy, times to event (disease progression and death) were studied through proportional hazard models, in relation to different prognostic factors, including a chromosome 13 fluorescence in situ hybridization (FISH) analysis using a D13S319 probe. Δ13 was detected in 42 patients (38%). Follow-up time among surviving patients and survival time were 48 ± 3 and 51 ± 7 months, respectively (median ± SE). In the univariate analysis, Δ13 was the most powerful adverse prognostic factor for all times to event, especially for the survival time (P < .0001) and was followed by β2-microglobulin (β2m) levels 2.5 mg/L or higher (P = .0001). The comparison of survival prognostic models including β2m 2.5 mg/L or greater and another factor favored the Δ13/β2m combination. In 22 patients (20%) with no unfavorable factor, the median survival time was not reached at 111 months. In contrast, among 55 patients (50%) with one unfavorable factor and 33 patients (30%) with 2 unfavorable factors, median survival times were 47.3 ± 4.6 months and 25.3 ± 3.2 months, respectively (P < .0001). We conclude that Δ13, adequately detected by FISH analysis, is a very strong factor related to poor survival, especially when associated with a β2m level of 2.5 mg/L or higher. Routine FISH Δ13 assessment is strongly recommended for patients considered for HDT.
Targeting the tyrosine kinase activity ofBCR-ABL represents a very promising therapeutic strategy in chronic myeloid leukemia (CML). Despite strong efficacy of the tyrosine kinase inhibitor STI571, ...resistance has been observed in a significant proportion of patients in advanced CML stage or in Ph-positive acute lymphoid leukemia (ALL). We investigated in this study the mechanism of resistance to STI571 through point mutations in the tyrosine kinase domain and/or BCR-ABL gene amplification in 24 patients (16 in chronic phase and 8 in accelerated phase of the disease) who obtained no cytogenetic response to STI571 treatment. Screening for the already-described Thr315Ile point mutation in the ABL domain using a reverse transcription polymerase chain reaction restriction fragment length polymorphism (RT-PCR-RFLP) technique, 3 patients showed a proportion of mutated transcript at the time of resistance. The same technique failed to detect mutation at diagnosis, but a specific allele-specific oligonucleotide (ASO)–PCR on DNA for the Thr315Ile mutation and, after sequencing, for 2 newly described Phe311Leu and Met351Thr substitutions, showed the presence of rare mutated cells prior to STI571 therapy. Furthermore, the increased proportion of mutated cells during treatment detected by ASO-PCR strongly suggested clonal selection by the functional inhibiting effect of these mutations. Finally, no BCR-ABL gene amplification was detected by fluorescent in situ hybridization (FISH) in the 24 STI571-resistant patients. Our data support that in CML patients treated with STI571, ABL mutations are not restricted to the accelerated phase of the disease and that, at least in some cases, mutations seem to occur prior to STI571 therapy, probably as second mutational events during the course of CML.
Prions are pathogens formed from abnormal conformers (PrP.sup.Sc) of the host-encoded cellular prion protein (PrP.sup.C). PrP.sup.Sc conformation to disease phenotype relationships extensively vary ...among prion strains. In particular, prions exhibit a strain-dependent tropism for lymphoid tissues. Prions can be composed of several substrain components. There is evidence that these substrains can propagate in distinct tissues (e.g. brain and spleen) of a single individual, providing an experimental paradigm to study the cause of prion tissue selectivity. Previously, we showed that PrP.sup.C expression levels feature in prion substrain selection in the brain. Transmission of sheep scrapie isolates (termed LAN) to multiple lines of transgenic mice expressing varying levels of ovine PrP.sup.C in their brains resulted in the phenotypic expression of the dominant sheep substrain in mice expressing near physiological PrP.sup.C levels, whereas a minor substrain replicated preferentially on high expresser mice. Considering that PrP.sup.C expression levels are markedly decreased in the spleen compared to the brain, we interrogate whether spleen PrP.sup.C dosage could drive prion selectivity. The outcome of the transmission of a large cohort of LAN isolates in the spleen from high expresser mice correlated with the replication rate dependency on PrP.sup.C amount. There was a prominent spleen colonization by the substrain preferentially replicating on low expresser mice and a relative incapacity of the substrain with higher-PrP.sup.C level need to propagate in the spleen. Early colonization of the spleen after intraperitoneal inoculation allowed neuropathological expression of the lymphoid substrain. In addition, a pair of substrain variants resulting from the adaptation of human prions to ovine high expresser mice, and exhibiting differing brain versus spleen tropism, showed different tropism on transmission to low expresser mice, with the lymphoid substrain colonizing the brain. Overall, these data suggest that PrP.sup.C expression levels are instrumental in prion lymphotropism.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Prions induce a fatal neurodegenerative disease in infected host brain based on the refolding and aggregation of the host-encoded prion protein PrP
C
into PrP
Sc
. Structurally distinct PrP
...Sc
conformers can give rise to multiple prion strains. Constrained interactions between PrP
C
and different PrP
Sc
strains can in turn lead to certain PrP
Sc
(sub)populations being selected for cross-species transmission, or even produce mutation-like events. By contrast, prion strains are generally conserved when transmitted within the same species, or to transgenic mice expressing homologous PrP
C
. Here, we compare the strain properties of a representative sheep scrapie isolate transmitted to a panel of transgenic mouse lines expressing varying levels of homologous PrP
C
. While breeding true in mice expressing PrP
C
at near physiological levels, scrapie prions evolve consistently towards different strain components in mice beyond a certain threshold of PrP
C
overexpression. Our results support the view that PrP
C
gene dosage can influence prion evolution on homotypic transmission.
Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can ...transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrP(c)), into a misfolded form, abnormal PrP (PrP(Sc)), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrP(Sc) detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrP(Sc) molecular features and "cases" that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrP(ARR) allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health.
Inflammasomes are intracellular protein complexes that sense microbial components and damage of infected cells. Following activation by molecules released by pathogens or injured cells, inflammasomes ...activate caspase-1, allowing secretion of the pro-inflammatory cytokines IL-1β and IL-18 from innate immune cells. Inflammasomes are also expressed in epithelial cells, where their function has attracted less attention. Nonetheless, depending on the tissue, epithelial inflammasomes can mediate inflammation, wound healing, and pain sensitivity. We review here recent findings on inflammasomes found in epithelial tissues, highlighting the importance of these protein complexes in the response of epithelial tissues to microbial infections.
Most chromosomal translocations in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) involve oncogenes that are either up-regulated or form part of new chimeric genes. The ...t(2;11)(p21;q23) translocation has been cloned in 19 cases of MDS and AML. In addition to this, we have shown that this translocation is associated with a strong up-regulation of miR-125b (from 6- to 90-fold). In vitro experiments revealed that miR-125b was able to interfere with primary human CD34+ cell differentiation, and also inhibited terminal (monocytic and granulocytic) differentiation in HL60 and NB4 leukemic cell lines. Therefore, miR-125b up-regulation may represent a new mechanism of myeloid cell transformation, and myeloid neoplasms carrying the t(2;11) translocation define a new clinicopathological entity.
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•Quantified PM2.5 components in Tehran and PMF was used for source apportionment.•Major PM2.5 mass constituents were organic matter, sulfate and EC.•8 identified factors were: TE, BB, ...Ind., nitrate, sulfate, dust, TNE, and HFC.•TE had 45% contribution to PM2.5 mass. Sulfate and nitrate were the next major contributors.•TE and BB were local sources, whereas dust, Ind. and HFC were regional sources.
With over 8 million inhabitants and 4 million motor vehicles on the streets, Tehran is one of the most crowded and polluted cities in the Middle East. Frequent exceedances of national daily PM2.5 limit have been reported in this city during the last decade, yet, the chemical composition and sources of fine particles are poorly determined. In the present study, 24-hour PM2.5 samples were collected at two urban sites during two separate campaigns, a one-year period from 2014 to 2015 and another three-month period at the beginning of 2017. Concentrations of organic carbon (OC), elemental carbon (EC), inorganic ions, trace metals and specific organic molecular markers were measured by chemical analysis of filter samples. The dominant mass components were organic matter (OM), sulfate and EC. With a 20% water-soluble organic carbon (WSOC) fraction, the predominance of primary anthropogenic sources (i.e. fossil fuel combustion) was anticipated. A positive matrix factorization (PMF) analysis using the ME-2 (Multilinear Engine-2) solver was then applied to this dataset. 5 factors were identified by Marker-PMF, named as traffic exhaust (TE), biomass burning (BB), industries (Ind.), nitrate-rich and sulfate-rich. Another 4 factors were identified by Metal-PMF, including, dust, vehicles (traffic non-exhaust, TNE), industries (Ind.) and heavy fuel combustion (HFC). Traffic exhaust was the dominant source with 44.5% contribution to total quantified PM2.5 mass. Sulfate-rich (24.2%) and nitrate-rich (18.4%) factors were the next major contributing sources. Dust (4.4%) and biomass burning (6.7%) also had small contributions while the total share of all other factors was < 2%. Investigating the correlations of different factors between the two sampling sites showed that traffic emissions and biomass burning were local, whereas dust, heavy fuel combustion and industrial sources were regional. Results of this study indicate that gas- and particle-phase pollutants emitted from fossil fuel combustion (mobile and stationary) are the principal origin of both primary and secondary fine aerosols in Tehran.
To date, bovine spongiform encephalopathy (BSE) and its human counterpart, variant Creutzfeldt-Jakob disease, have been associated with a single prion strain. This strain is characterised by a unique ...and remarkably stable biochemical profile of abnormal protease-resistant prion protein (PrP(res)) isolated from brains of affected animals or humans. However, alternate PrP(res) signatures in cattle have recently been discovered through large-scale screening. To test whether these also represent separate prion strains, we inoculated French cattle isolates characterised by a PrP(res) of higher apparent molecular mass--called H-type--into transgenic mice expressing bovine or ovine PrP. All mice developed neurological symptoms and succumbed to these isolates, showing that these represent a novel strain of infectious prions. Importantly, this agent exhibited strain-specific features clearly distinct from that of BSE agent inoculated to the same mice, which were retained on further passage. Moreover, it also differed from all sheep scrapie isolates passaged so far in ovine PrP-expressing mice. Our findings therefore raise the possibility that either various prion strains may exist in cattle, or that the BSE agent has undergone divergent evolution in some animals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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