Multi-Informative and Specific Detection of Blood in Fingermarks via MALDI-MS Based Strategies

Currently employed enhancement and detection techniques for blood are not confirmatory due to targeting generic compound classes like proteins. As such, they are not sufficiently specific and are prone to false positives. The aim of this work was to confidently determine whether a crime scene sample is in fact blood and more specifically human blood. To achieve this, an in-solution bottom up proteomic approach was developed, targeting blood-specific proteins and employing MALDI-MS. The work was developed further to devise a protocol for proteomic in situ analysis of bloodied fingermarks with MALDI-MS imaging, enabling the mapping of blood peptides to fingermark ridges and thus establishing a strong link between the suspect and the event of bloodshed. Putative peptide identifications were made for signals originating from a number of different blood-specific proteins, including not only the most abundant blood proteins like haemoglobin, but also several other proteins (e.g. complement C3 and hemopexin). To further validate the method, a blind study was conducted analysing unknown samples ranging from different species' blood and human biofluids to other substances known to produce false positives with conventional techniques. Employing MALDI-MS, it was possible to confidently identify human blood samples of up to 34 years in age. This is potentially a huge step forward in the forensic analysis of suspected blood samples and shows potential for re-analysis of cold case samples or samples of disputed origin. It was found in this study that further optimisation of the data analysis approach is required for provenance determination of animal blood samples. Traditionally, establishing the order of deposition of fingermarks associated with blood is difficult and subjective. Infinite focus microscopy was investigated for its potential to facilitate quantitative differentiation between the different deposition scenarios. However, results were highly dependent on the surface of deposition and thus the technique was shown to be unsuitable due to the wide range of surfaces potentially encountered in a forensic investigation

Efficacy and safety of avapritinib in advanced systemic mastocytosis:interim analysis of the phase 2 PATHFINDER trial

Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM (n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM–Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met (P = 1.6 × 10(-9)), with an ORR of 75% (95% confidence interval 57–89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of ≥50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade ≥3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM

Tyrosine kinase chromosomal translocations mediate distinct and overlapping gene regulation events

<p>Abstract</p> <p>Background</p> <p>Leukemia is a heterogeneous disease commonly associated with recurrent chromosomal translocations that involve tyrosine kinases including BCR-ABL, TEL-PDGFRB and TEL-JAK2. Most studies on the activated tyrosine kinases have focused on proximal signaling events, but little is known about gene transcription regulated by these fusions.</p> <p>Methods</p> <p>Oligonucleotide microarray was performed to compare mRNA changes attributable to BCR-ABL, TEL-PDGFRB and TEL-JAK2 after 1 week of activation of each fusion in Ba/F3 cell lines. Imatinib was used to control the activation of BCR-ABL and TEL-PDGFRB, and TEL-JAK2-mediated gene expression was examined 1 week after Ba/F3-TEL-JAK2 cells were switched to factor-independent conditions.</p> <p>Results</p> <p>Microarray analysis revealed between 800 to 2000 genes induced or suppressed by two-fold or greater by each tyrosine kinase, with a subset of these genes commonly induced or suppressed among the three fusions. Validation by Quantitative PCR confirmed that eight genes (Dok2, Mrvi1, Isg20, Id1, gp49b, Cxcl10, Scinderin, and collagen Vα1(Col5a1)) displayed an overlapping regulation among the three tested fusion proteins. Stat1 and Gbp1 were induced uniquely by TEL-PDGFRB.</p> <p>Conclusions</p> <p>Our results suggest that BCR-ABL, TEL-PDGFRB and TEL-JAK2 regulate distinct and overlapping gene transcription profiles. Many of the genes identified are known to be involved in processes associated with leukemogenesis, including cell migration, proliferation and differentiation. This study offers the basis for further work that could lead to an understanding of the specificity of diseases caused by these three chromosomal translocations.</p

A Mammalian Conserved Element Derived from SINE Displays Enhancer Properties Recapitulating Satb2 Expression in Early-Born Callosal Projection Neurons

Short interspersed repetitive elements (SINEs) are highly repeated sequences that account for a significant proportion of many eukaryotic genomes and are usually considered “junk DNA”. However, we previously discovered that many AmnSINE1 loci are evolutionarily conserved across mammalian genomes, suggesting that they may have acquired significant functions involved in controlling mammalian-specific traits. Notably, we identified the AS021 SINE locus, located 390 kbp upstream of Satb2. Using transgenic mice, we showed that this SINE displays specific enhancer activity in the developing cerebral cortex. The transcription factor Satb2 is expressed by cortical neurons extending axons through the corpus callosum and is a determinant of callosal versus subcortical projection. Mouse mutants reveal a crucial function for Sabt2 in corpus callosum formation. In this study, we compared the enhancer activity of the AS021 locus with Satb2 expression during telencephalic development in the mouse. First, we showed that the AS021 enhancer is specifically activated in early-born Satb2+ neurons. Second, we demonstrated that the activity of the AS021 enhancer recapitulates the expression of Satb2 at later embryonic and postnatal stages in deep-layer but not superficial-layer neurons, suggesting the possibility that the expression of Satb2 in these two subpopulations of cortical neurons is under genetically distinct transcriptional control. Third, we showed that the AS021 enhancer is activated in neurons projecting through the corpus callosum, as described for Satb2+ neurons. Notably, AS021 drives specific expression in axons crossing through the ventral (TAG1−/NPY+) portion of the corpus callosum, confirming that it is active in a subpopulation of callosal neurons. These data suggest that exaptation of the AS021 SINE locus might be involved in enhancement of Satb2 expression, leading to the establishment of interhemispheric communication via the corpus callosum, a eutherian-specific brain structure

Institutional Environments for Enabling Agricultural Technology Innovations: The Role of Land Rights in Ethiopia, Ghana, India and Bangladesh

Land rights are essential assets for improving the livelihoods of the rural poor. This literature based paper shed light to some land rights issues that are crucial for the effectiveness and sustainability of implementing technological innovations in marginalized rural areas of Ethiopia, Ghana, India and Bangladesh. By analysing country specific land right regimes, this paper aims to understand what institutional conditions might constitute barriers to the effective implementation of technological innovations and how they might be overcome. Land rights issues considered in this paper include public and private ownership of land in Ethiopia, customary and statutory law in Ghana, and gender equality and land rights in India and Bangladesh. A better understanding of institutional barriers for the effective implementation of technological innovations is a precondition for complementing technological with enabling institutional innovations and for improving priority setting, targeting and sequencing in the implementation of productivity increasing development measures

Social Safety Nets for Food and Nutritional Security in India

This paper brings together existing literature on the Mahatma Gandhi National Rural Employment Guarantee Act (MGNRGEA) and the Public Distribution System (PDS) in India, offering a narrative review of the evidence on impacts on food security, health and nutrition of beneficiaries. Both programs operate on a large scale and have the capacity to impact the factors leading to undernutrition. It is evident that despite the deficiencies in implementation, both the MGNREGA and the PDS are inclusive and reach the poor and the marginalized who are likely to also experience greater undernutrition and poor health. Data challenges have however prevented researchers from conducting studies that assess the ultimate impact of these two large-scale programs on health and nutrition. The evidence that exists suggests largely positive impacts indicating a clear potential to make these programs more nutrition sensitive not just by incorporating elements that would explicitly address nutritional concerns but also by directing specific attention to innovations that strengthen critical complementarities and synergies that exist between the two programs

The impact of the spring 2020 snowmelt floods on physicochemical conditions in three Norwegian river-fjord-coastal systems

Project Manager Heleen de WitDue to very high snow accumulation in the winter of 2019/2020, the Norwegian Water Resources and Energy Directorate (NVE) in late May 2020 issued flood forecasts predicting extremely high flood risk for parts of northern Norway and high flood risk for rivers in south-eastern Norway with mountainous catchments. To capture impacts of these potentially extreme snowmelt floods on water chemistry in rivers and coastal waters, extra sampling campaigns were carried out in three selected river-fjord systems: Glomma river-Ytre Oslofjord-Skagerrak in southern Norway, and the Målselv river-Målselvfjord-Straumsfjorden and Tana river-Tanafjord systems in northern Norway. The overarching goal was to study the impact of the 2020 spring freshet (i.e. snowmelt flood) on river water chemistry, land-ocean fluxes, and physicochemical conditions in coastal waters. In this report we describe between-site differences and seasonal patterns in river and coastal water chemistry based on existing data from national river (2016–2020) and coastal (2017–2020) monitoring in the three study regions, and then use these to provide context for the data from the spring 2020-sampling campaign, with a focus on suspended particulate matter (SPM), dissolved organic carbon (DOC), and nutrients. This report also highlights the complexity of identifying climate change impacts along the terrestrial-freshwater-marine continuum and the need for tighter cross-disciplinary and cross-ecosystem integration between monitoring programmes.publishedVersio

Active Alu Element “A-Tails”: Size Does Matter

Long and short interspersed elements (LINEs and SINEs) are retroelements that make up almost half of the human genome. L1 and Alu represent the most prolific human LINE and SINE families, respectively. Only a few Alu elements are able to retropose, and the factors determining their retroposition capacity are poorly understood. The data presented in this paper indicate that the length of Alu “A-tails” is one of the principal factors in determining the retropositional capability of an Alu element. The A stretches of the Alu subfamilies analyzed, both old (Alu S and J) and young (Ya5), had a Poisson distribution of A-tail lengths with a mean size of 21 and 26, respectively. In contrast, the A-tails of very recent Alu insertions (disease causing) were all between 40 and 97 bp in length. The L1 elements analyzed displayed a similar tendency, in which the “disease”-associated elements have much longer A-tails (mean of 77) than do the elements even from the young Ta subfamily (mean of 41). Analysis of the draft sequence of the human genome showed that only about 1000 of the over one million Alu elements have tails of 40 or more adenosine residues in length. The presence of these long A stretches shows a strong bias toward the actively amplifying subfamilies, consistent with their playing a major role in the amplification process. Evaluation of the 19 Alu elements retrieved from the draft sequence of the human genome that are identical to the Alu Ya5a2 insert in the NF1 gene showed that only five have tails with 40 or more adenosine residues. Sequence analysis of the loci with the Alu elements containing the longest A-tails (7 of the 19) from the genomes of the NF1 patient and the father revealed that there are at least two loci with A-tails long enough to serve as source elements within our model. Analysis of the A-tail lengths of 12 Ya5a2 elements in diverse human population groups showed substantial variability in both the Alu A-tail length and sequence homogeneity. On the basis of these observations, a model is presented for the role of A-tail length in determining which Alu elements are active. [The sequence data from this study have been submitted to GenBank under accession nos. AF504933–AF505511.