Managing alloimmunization, delayed hemolytic transfusion reactions, and hyper-hemolysis in sickle cell disease

Sickle cell disease (SCD) is an inherited blood disorder in which polymerization of a mutated form of hemoglobin results in a sickled shape of red blood cells, leading to anemia due to premature destruction of RBCs. Other morbidities include end-organ damage, pain attacks known as “sickle cell crisis,” bacterial infections, and stroke. Transfusion therapy remains a necessary treatment of sickle cell disease. Transfusions given to lower the levels of sickle RBCs and viscosity have shown to decrease the risk of stroke by 90% during clinical trials. However, chronically transfused patients can become alloimmunized and develop delayed hemolytic transfusion reactions (DHTR), a life-threatening condition. The presentation of DHTR can vary, and its severity is unpredictable. In the most severe cases, patients destroy their own RBCs along with the transfused RBCs, a condition known as hyper-hemolysis. Additional transfusions can aggravate these symptoms and lead to death. Clinicians’ awareness of DHTR events is poor because its clinical presentations mimic those of vaso-occlusive crisis. Furthermore, immunohematology at times detect no newly formed antibodies. Mortality due to DHTR have been reported to be as high as 11.5%. Currently, 5.4 million people suffer from sickle cell disease. An overwhelming 80% of SCD occurs in Sub-Saharan Africa, while also occurring frequently in people of African origin living in other parts of the world. Annually, over 100,000 patients are affected by SCD, utilizing over one billion dollars per year in healthcare costs. Lastly, current projections estimate that by 2050 the number of newborns with sickle cell disease will exceed 400,000. While there are no drugs that specifically target DHTR, immunosuppressants such as intravenous immunoglobulins, steroids, eculizumab, and tocilizumab have shown to improve outcomes in DHTR. However, these treatments may prove to be insufficient. Moreover, numerous adverse health effects are associated with using immunosuppressants, including exacerbation of vaso-occlusive pain and hemolytic anemia already present in SCD patients. Currently, alloimmunization can be prevented by extended-matching of blood antigen, increasing blood donations from Africa Americans and other minority groups, and the use of rituximab. While hematopoietic stem cell transplantation remains a viable alternative to transfusing therapy, it remains highly under-utilized. This literature review aims to evaluate the current prevention and treatment methods used to manage DHTR to expose gaps in knowledge and identify ways to improve clinical outcomes in SCD patients. Results suggest: (1) While it is not cost-effective to implement extended matching in all SCD patients, there is potential in strategies to increase blood donation in minority groups. Genotyping of blood antigens may also be considered. (2) Treatment options are sorely lacking for DHTR. Case studies document positive outcomes using immunosuppressants, but there are few clinical trials and evidence-based studies to confirm their efficacy in larger cohorts. (3) Effective treatment of DHTR relies on prospective studies that further elucidate the pathophysiology of alloimmunization and DHTR. (4) The lack of effective treatments for DHTR can be attributed to structural violence. Advocacy and awareness are instrumental in improving care for DHTR and SCD

PHYSICOCHEMICAL AND FUNCTIONAL PROPERTY MODIFICATION OF MYOFIBRILLAR PROTEIN BY PHENOLIC COMPOUNDS UNDER OXIDATIVE STRESS

Polyphenol-rich spices and extracts of phenolic compounds are widely utilized in meat processing to modify product flavors. Chemically, polyphenols are reactive with myofibrillar protein (MP), the most functional fraction of all muscle proteins responsible for texture development in comminuted meat products. Such protein–polyphenol interaction is prevalent under oxidative conditions that are common in meat processing. As a large group of phytochemicals with diverse structures, phenolic compounds are known to interact with MP with varying efficacies. Yet, the structure-function relationship of polyphenols in eliciting modification of MP is poorly understood. The overall objective of this dissertation research was to elucidate the effect of structurally related phytophenols on the physicochemical properties of MP and resultant changes in protein functionalities, i.e., gelation and emulsification. To establish appropriate testing conditions, a mild oxidative environment was introduced using glucose oxidase (GOx), and the simplest phenolic compound, gallic acid (GA), was used to investigate the effect on the physicochemical and gelling behavior of MP. Compared with non-oxidized (control) MP, GOx-mediated oxidation facilitated both covalent and noncovalent interactions between GA (6, 30, and 60 μmol/g protein) and protein through promoting protein structural unfolding. Such modifications significantly enhanced the gelling capacity of MP, which was evidenced by up to 86% and 53% increases (P \u3c 0.05) in gel elasticity (G′) and breaking strength, respectively. Based on the above observations, six structurally related monophenolic acids varying in hydroxyl substitution and sidechain groups, i.e., GA, syringic acid (SA), coumaric acid (CMA), caffeic acid (CFA), ferulic acid (FA), and chlorogenic acid (CA), were examined for their effects on MP conformation and gelation under GOx oxidative stress. The elasticity and breaking strength of MP gels were markedly enhanced by all phenolic acids, of which GA and CA induced the highest final G′ values of 291 and 281 Pa (P \u3c 0.05), respectively, as compared with 214 Pa of the control MP sample without phenolic addition. Different reaction modes were evident for these two most effective phenolic acids in improving protein gelation. With the least structural hinderance, the smallest GA facilitated protein cross-linking through covalent adduction to amino acid sidechains. On the other hand, having a bulky sidechain group, CA was the most effective in promoting protein unfolding due to the multiple functional groups, including 5 hydroxyl groups and 1 extra hydrocarbon ring (quinic acid). The findings of structure-dependency of phenolic activity prompted the following experiment where phenolic compounds with more than one phenol structures were included to investigate their influence on MP functionalities. Here, in addition to three monophenols, i.e., GA, CA, and propyl gallate (PG), two diphenols, i.e., quercetin (QT) and catechin (CC), and one triphenol, i.e., (–)-epigallocatechin-3-gallate (EGCG), were selected to further explore the structure-activity relationship of phenolic compounds on MP functionalities under GOx oxidation. MP-stabilized oil-in-water emulsions were prepared to assess protein emulsifying properties, and an emulsion-filled composite gel system was adopted as a model to mimic comminuted meat products in which MP acted as both an emulsifier and a building block for the protein matrix within the gel. In the emulsion system, phenolic compounds with less polarity, i.e., PG, QT, and CC, significantly improved the emulsifying capacity of MP by increasing protein partition at the oil-water interface by 15, 17, and 23%, respectively (P \u3c 0.05). In the MP–emulsion composite gel system, all three monophenols (GA, CA, and PG) and the diphenol QT increased the MP gel strength to a greater extent than CC (diphenol) and EGCG (triphenol). The flavanol structure in CC appeared to interfere with gel structure development. The multiple phenol structures in EGCG caused protein aggregation so severe that both emulsifying and gelling properties of MP were weakened. Lipid oxidation was retarded by all phenols in MP–emulsion composite gels during storage at 4 °C for 7 days with PG and QT being the most effective. The above findings established that the type and size of the sidechain groups, the number of hydroxyl attached to the benzene ring, as well as the number of the phenol moiety have an important role in affecting phytophenol–MP interaction and the protein functionality under oxidative condition. Small-sized phenolic compounds tend to promote MP gelation and emulsification, and larger sized (such as EGCG) exhibited negative effects due to the propensity to facilitate extensive protein aggregation

Mapping applications onto FPGA-centric clusters

High Performance Computing (HPC) is becoming increasingly important throughout science and engineering as ever more complex problems must be solved through computational simulations. In these large computational applications, the latency of communication between processing nodes is often the key factor that limits performance. An emerging alternative computer architecture that addresses the latency problem is the FPGA-centric cluster (FCC); in these systems, the devices (FPGAs) are directly interconnected and thus many layers of hardware and software are avoided. The result can be scalability not currently achievable with other technologies. In FCCs, FPGAs serve multiple functions: accelerator, network interface card (NIC), and router. Moreover, because FPGAs are configurable, there is substantial opportunity to tailor the router hardware to the application; previous work has demonstrated that such application-aware configuration can effect a substantial improvement in hardware efficiency. One constraint of FCCs is that it is convenient for their interconnect to be static, direct, and have a two or three dimensional mesh topology. Thus, applications that are naturally of a different dimensionality (have a different logical topology) from that of the FCC must be remapped to obtain optimal performance. In this thesis we study various aspects of the mapping problem for FCCs. There are two major research thrusts. The first is finding the optimal mapping of logical to physical topology. This problem has received substantial attention by both the theory community, where topology mapping is referred to as graph embedding, and by the High Performance Computing (HPC) community, where it is a question of process placement. We explore the implications of the different mapping strategies on communication behavior in FCCs, especially on resulting load imbalance. The second major research thrust is built around the hypothesis that applications that need to be remapped (due to differing logical and physical topologies) will have different optimal router configurations from those applications that do not. For example, due to remapping, some virtual or physical communication links may have little occupancy; therefore fewer resources should be allocated to them. Critical here is the creation of a new set of parameterized hardware features that can be configured to best handle load imbalances caused by remapping. These two thrusts form a codesign loop: certain mapping algorithms may be differentially optimal due to application-aware router reconfiguration that accounts for this mapping. This thesis has four parts. The first part introduces the background and previous work related to communication in general and, in particular, how it is implemented in FCCs. We build on previous work on application-aware router configuration. The second part introduces topology mapping mechanisms including those derived from graph embeddings and a greedy algorithm commonly used in HPC. In the third part, topology mappings are evaluated for performance and imbalance; we note that different mapping strategies lead to different imbalances both in the overall network and in each node. The final part introduces reconfigure router design that allocates resources based on different imbalance situations caused by different mapping behaviors

Predictability of Stock Returns and Open Market Repurchases

We find that stock returns are driven, at least in part, by open market share repurchases by the firm. We also find that the amount of open market repurchases can be predicted, at least in part, by the pre-repurchase stock performance. Further analysis reveals that post-announcement return anomalies are more significant for firms that follow their announcements by conducting actual repurchases during the four quarters following the announcement quarter. In addition, the amount of shares repurchased is a better predictor of returns for firms that announce only once within one year

Animal and Plant Protein Oxidation: Chemical and Functional Property Significance

Protein oxidation, a phenomenon that was not well recognized previously but now better understood, is a complex chemical process occurring ubiquitously in food systems and can be induced by processing treatments as well. While early research concentrated on muscle protein oxidation, later investigations included plant, milk, and egg proteins. The process of protein oxidation involves both radicals and nonradicals, and amino acid side chain groups are usually the site of initial oxidant attack which generates protein carbonyls, disulfide, dityrosine, and protein radicals. The ensuing alteration of protein conformational structures and formation of protein polymers and aggregates can result in significant changes in solubility and functionality, such as gelation, emulsification, foaming, and water-holding. Oxidant dose-dependent effects have been widely reported, i.e., mild-to-moderate oxidation may enhance the functionality while strong oxidation leads to insolubilization and functionality losses. Therefore, controlling the extent of protein oxidation in both animal and plant protein foods through oxidative and antioxidative strategies has been of wide interest in model system as well in in situ studies. This review presents a historical perspective of food protein oxidation research and provides an inclusive discussion of the impact of chemical and enzymatic oxidation on functional properties of meat, legume, cereal, dairy, and egg proteins based on the literature reports published in recent decades

Generating Linear programming Instances with Controllable Rank and Condition Number

Instances generation is crucial for linear programming algorithms, which is necessary either to find the optimal pivot rules by training learning method or to evaluate and verify corresponding algorithms. This study proposes a general framework for designing linear programming instances based on the preset optimal solution. First, we give a constraint matrix generation method with controllable condition number and rank from the perspective of matrix decomposition. Based on the preset optimal solution, the bounded feasible linear programming instance is generated with the right-hand side and objective coefficient satisfying the original and dual feasibility. In addition, we provide three kind of neighborhood exchange operators and prove that instances generated under this method can fill the whole feasible and bounded case space of linear programming. We experimentally validate that the proposed schedule can generate more controllable linear programming instances, while neighborhood exchange operator can construct more complex instances.Comment: 28 page

Potential pitfalls in the accuracy of analysis of natural sense-antisense RNA pairs by reverse transcription-PCR

<p>Abstract</p> <p>Background</p> <p>The ability to accurately measure patterns of gene expression is essential in studying gene function. The reverse transcription polymerase chain reaction (RT-PCR) has become the method of choice for the detection and measurement of RNA expression patterns in both cells and small quantities of tissue. Our previous results show that there is a significant production of primer-independent cDNA synthesis using a popular RNase H^-RT enzyme. A PCR product was amplified from RT reactions that were carried out without addition of RT-primer. This finding jeopardizes the accuracy of RT-PCR when analyzing RNA that is expressed in both orientations. Current literature findings suggest that naturally occurring antisense expression is widespread in the mammalian transcriptome and consists of both coding and non-coding regulatory RNA. The primary purpose of this present study was to investigate the occurrence of primer-independent cDNA synthesis and how it may influence the accuracy of detection of sense-antisense RNA pairs.</p> <p>Results</p> <p>Our findings on cellular RNA and <it>in vitro </it>synthesized RNA suggest that these products are likely the results of RNA self-priming to generate random cDNA products, which contributes to the loss of strand specificity. The use of RNase H⁺RT enzyme and carrying the RT reaction at high temperature (50°C) greatly improved the strand specificity of the RT-PCR detection.</p> <p>Conclusion</p> <p>While RT PCR is a basic method used for the detection and quantification of RNA expression in cells, primer-independent cDNA synthesis can interfere with RT specificity, and may lead to misinterpretation of the results, especially when both sense and antisense RNA are expressed. For accurate interpretation of the results, it is essential to carry out the appropriate negative controls.</p

Security boundaries of an optical power limiter for protecting quantum key distribution systems

Unauthorized light injection has always been a vital threat to the practical security of a quantum key distribution (QKD) system. An optical power limiter (OPL) based on the thermo-optical defocusing effect has been proposed and implemented, limiting the injected hacking light. As a hardware countermeasure, the performance of the OPL under various light-injection attacks shall be tested to clarify the security boundary before being widely deployed. To investigate the OPL's security boundary in quantum cryptography, we comprehensively test and analyse the behavior of OPL under continuous-wave (c.w.) light-injection attacks and pulse illumination attacks with pulses' repetition rate at 0.5-Hz,40-MHz, and 1-GHz. The testing results illuminate the security boundary of the OPL, which allows one to properly employ the OPL in the use cases. The methodology of testing and analysis proposed here is applicable to other power-limitation components in a QKD system.Comment: 14 pages, 13 figure

Ghrelin regulates hyperactivity-like behaviors via growth hormone signaling pathway in zebrafish (Danio rerio)

IntroductionGhrelin is originally identified as the endogenous ligand for the growth hormone secretagogue receptor (GHSR) and partially acts by stimulating growth hormone (GH) release. Our previous studies have identified GHRELIN as a novel susceptibility gene for human attention-deficit hyperactivity disorder (ADHD), and ghrelin-depleted zebrafish (Danio rerio) display ADHD-like behaviors. However, the underlying molecular mechanism how ghrelin regulates hyperactivity-like behaviors is not yet known.ResultsHere, we performed RNA-sequencing analysis using adult ghrelinΔ/Δ zebrafish brains to investigate the underlying molecular mechanisms. We found that gh1 mRNA and genes related to the gh signaling pathway were significantly reduced at transcriptional expression levels. Quantitative polymerase chain reaction (qPCR) was performed and confirmed the downregulation of gh signaling pathway-related genes in ghrelinΔ/Δ zebrafish larvae and the brain of adult ghrelinΔ/Δ zebrafish. In addition, ghrelinΔ/Δ zebrafish displayed hyperactive and hyperreactive phenotypes, such as an increase in motor activity in swimming test and a hyperreactive phenotype under light/dark cycle stimulation, mimicking human ADHD symptoms. Intraperitoneal injection of recombinant human growth hormone (rhGH) partially rescued the hyperactivity and hyperreactive-like behaviors in ghrelin mutant zebrafish. ConclusionOur results indicated that ghrelin may regulate hyperactivity-like behaviors by mediating gh signaling pathway in zebrafish. And the protective effect of rhGH on ghrelinΔ/Δ zebrafish hyperactivity behavior provides new therapeutic clues for ADHD patients