Influence of donor-recipient sex on engraftment of normal and leukemia stem cells in xenotransplantation.

Immunodeficient mouse models are widely used for the assessment of human normal and leukemic stem cells. Despite the advancements over the years, reproducibility, as well as the differences in the engraftment of human cells in recipient mice remains to be fully resolved. Here, we used various immunodeficient mouse models to characterize the effect of donor-recipient sex on the engraftment of the human leukemic and healthy cells. Donor human cells and recipient immunodeficient mice demonstrate sex-specific engraftment levels with significant differences observed in the lineage output of normal CD34+ hematopoietic stem and progenitor cells upon xenotransplantation. Intriguingly, human female donor cells display heightened sensitivity to the recipient mice's gender, influencing their proliferation and resulting in significantly increased engraftment in female recipient mice. Our study underscores the intricate interplay taking place between donor and recipient characteristics, shedding light on important considerations for future studies, particularly in the context of pre-clinical research.

Assessment of consolidative multi-criteria decision making (C-MCDM) algorithms for optimal mapping of polymer materials in additive manufacturing: A case study of orthotic application.

Objective: The objectives of this research are twofold. The primary goal is to introduce, investigate, and contrast consolidative multi-criteria decision-making (C-MCDM) approaches. The second objective is the investigation of five alternative additive manufacturing materials. Methods: It integrates the subjective and objective weights using the Bayes hypothesis in conjunction with a normal method. Chang's Extent Analysis Method under fuzzy logic is used to estimate subjective weights and the CRITIC approach is used for assessing objective weights. Ranking techniques, including the simple ranking process (SRP), multi-objective optimization based on ratio analysis (MOORA), measurement alternatives and ranking according to compromise solution (MARCOS), and technique for order preference by similarity to ideal solution (TOPSIS) are applied. It also encompasses sensitivity analysis based on Kendall's coefficient of concordance and rank reversal phenomenon analysis. Spearman's rank correlation coefficient, a weighted rank measure of correlation, and rank similarity coefficient are among the metrics used to evaluate agreement between different approaches. It entails gathering expert opinions regarding the importance of various criteria as well as conducting extensive experiments. Results: The findings of the study indicate that polylactic acid is the best material to use for orthoses. When compared to the other MCDM approaches being discussed, SRP is the most reliable approach. It is also demonstrated that the SRP, MARCOS, and TOPSIS methods are rank reversal-free. Furthermore, SRP exhibits a very poor association with the TOPSIS technique but a strong correlation with the MOORA and MARCOS approaches. Conclusions: To ensure results reliability, it is necessary to consider both the subjectivity and objectivity of weights as well as apply multiple MCDM methodologies in addition to sensitivity analysis.

Predicting Mechanical Properties of Polymer Materials Using Rate-Dependent Material Models: Finite Element Analysis of Bespoke Upper Limb Orthoses.

Three-dimensional printing-especially with fused deposition modeling (FDM)-is widely used in the medical field as it enables customization. FDM is versatile owing to the availability of various materials, but selecting the appropriate material for a certain application can be challenging. Understanding materials' mechanical behaviors, particularly those of polymeric materials, is vital to determining their suitability for a given application. Physical testing with universal testing machines is the most used method for determining the mechanical behaviors of polymers. This method is resource-intensive and requires cylinders for compression testing and unique dumbbell-shaped specimens for tensile testing. Thus, a specialized fixture must be designed to conduct mechanical testing for the customized orthosis, which is costly and time-consuming. Finite element (FE) analysis using an appropriate material model must be performed to identify the mechanical behaviors of a customized shape (e.g., an orthosis). This study analyzed three material models, namely the Bergström-Boyce (BB), three-network (TN), and three-network viscoplastic (TNV) models, to determine the mechanical behaviors of polymer materials for personalized upper limb orthoses and examined three polymer materials: PLA, ABS, and PETG. The models were first calibrated for each material using experimental data. Once the models were calibrated and found to fit the data appropriately, they were employed to examine the customized orthosis's mechanical behaviors through FE analysis. This approach is innovative in that it predicts the mechanical characteristics of a personalized orthosis by combining theoretical and experimental investigations.

An Insight into the Characteristics of 3D Printed Polymer Materials for Orthoses Applications: Experimental Study.

Knee orthoses assist patients with impaired gait through the amendment of knee abnormalities, restoration of mobility, alleviation of pain, shielding, and immobilization. The inevitable issues with laborious traditional plaster molding procedures for orthoses can be resolved with 3D printing. However, a number of challenges have limited the adoption of 3D printing, the most significant of which is the proper material selection for orthoses. This is so because the material used to make an orthosis affects its strength, adaptability, longevity, weight, moisture response, etc. This study intends to examine the mechanical, physical, and dimensional characteristics of three-dimensional (3D) printing materials (PLA, ABS, PETG, TPU, and PP). The aim of this investigation is to gain knowledge about these materials' potential for usage as knee orthosis materials. Tensile testing, Olympus microscope imaging, water absorption studies, and coordinate measuring machine-based dimension analysis are used to characterize the various 3D printing materials. Based on the investigation, PLA outperforms all other materials in terms of yield strength (25.98 MPa), tensile strength (30.89 MPa), and shrinkage (0.46%). PP is the least water absorbent (0.15%) and most flexible (407.99%); however, it is the most difficult to fabricate using 3D printing. When producing knee orthoses with 3D printing, PLA can be used for the orthosis frame and other structural elements, PLA or ABS for moving parts like hinges, PP for padding, and TPU or PP for the straps. This study provides useful information for scientists and medical professionals who are intrigued about various polymer materials for 3D printing and their effective utilization to fabricate knee orthoses.

Polyether-Ether-Ketone (PEEK) and Its 3D-Printed Quantitate Assessment in Cranial Reconstruction.

Three-dimensional (3D) printing, medical imaging, and implant design have all advanced significantly in recent years, and these developments may change how modern craniomaxillofacial surgeons use patient data to create tailored treatments. Polyether-ether-ketone (PEEK) is often seen as an attractive option over metal biomaterials in medical uses, but a solid PEEK implant often leads to poor osseointegration and clinical failure. Therefore, the objective of this study is to demonstrate the quantitative assessment of a custom porous PEEK implant for cranial reconstruction and to evaluate its fitting accuracy. The research proposes an efficient process for designing, fabricating, simulating, and inspecting a customized porous PEEK implant. In this study, a CT scan is utilized in conjunction with a mirrored reconstruction technique to produce a skull implant. In order to foster cell proliferation, the implant is modified into a porous structure. The implant's strength and stability are examined using finite element analysis. Fused filament fabrication (FFF) is utilized to fabricate the porous PEEK implants, and 3D scanning is used to test its fitting accuracy. The results of the biomechanical analysis indicate that the highest stress observed was approximately 61.92 MPa, which is comparatively low when compared with the yield strength and tensile strength of the material. The implant fitting analysis demonstrates that the implant's variance from the normal skull is less than 0.4436 mm, which is rather low given the delicate anatomy of the area. The results of the study demonstrate the implant's endurance while also increasing the patient's cosmetic value.

Finite Element Analysis of Upper Limb Splint Designs and Materials for 3D Printing.

Three-dimensional (3D) printed splints must be lightweight and adequately ventilated to maximize the patient's convenience while maintaining requisite strength. The ensuing loss of strength has a substantial impact on the transformation of a solid splint model into a perforated or porous model. Thus, two methods for making perforations-standard approach and topological optimization-are investigated in this study. The objective of this research is to ascertain the impact of different perforation shapes and their distribution as well as topology optimization on the customized splint model. The solid splint models made of various materials have been transformed into porous designs to evaluate their strength by utilizing Finite Element (FE) simulation. This study will have a substantial effect on the designing concept for medical devices as well as other industries such as automobiles and aerospace. The novelty of the research refers to creating the perforations as well as applying topology optimization and 3D printing in practice. According to the comparison of the various materials, PLA had the least amount of deformation and the highest safety factor for all loading directions. Additionally, it was shown that all perforation shapes behave similarly, implying that the perforation shape's effect is not notably pronounced. However, square perforations seemed to perform the best out of all the perforation shape types. It was also obvious that the topology-optimized hand splint outperformed that with square perforations. The topology-optimized hand splint weighs 26% less than the solid splint, whereas the square-perforated hand splint weighs roughly 12% less. Nevertheless, the user must choose which strategy (standard perforations or topology optimization) to employ based on the available tools and prerequisites.

Performance Evaluation of Input Power of Diode Laser on Machined Leather Specimen in Laser Beam Cutting Process.

Numerous industries, including footwear, handicrafts, and the automobile industry, utilize leather materials. The main goal of this study was to investigate the effect of input power of the diode laser in laser cutting on vegetable chrome tanned buffalo leather to enhance the cutting process. In the present investigation, carbonization, kerf width, and material removal rate (MRR) were taken as performance measures. The diode-based laser beam machining was designed and fabricated with 2.5 W, 5.5 W, and 20 W diode laser to cut vegetable chrome tanned leather. The high-intensity 20 W diode laser produced lower carbonization, lower kerf width, and higher material removal rate compared with the 2.5 W and 5.5 W diodes. This improved performance was due to the adjustable features associated with this diode laser actuation in the form of circular shape with adjustable diameter. A high power with a lower spot size under pulsed mode can produce higher power density. Since a higher power density can establish less interaction time, it produces lower carbonization. Due to the ability of the 20 W diode laser driver to control the beam shape and size, it could produce a lower kerf width and higher MRR. The optimal parameters for cutting chrome vegetable tanned cow leather were a standoff distance of 18 mm, feed rate of 200 mm/min, and duty cycle of 70%.

Vitamin B5 and succinyl-CoA improve ineffective erythropoiesis in SF3B1-mutated myelodysplasia.

Patients with myelodysplastic syndrome and ring sideroblasts (MDS-RS) present with symptomatic anemia due to ineffective erythropoiesis that impedes their quality of life and increases morbidity. More than 80% of patients with MDS-RS harbor splicing factor 3B subunit 1 (SF3B1) mutations, the founder aberration driving MDS-RS disease. Here, we report how mis-splicing of coenzyme A synthase (COASY), induced by mutations in SF3B1, affects heme biosynthesis and erythropoiesis. Our data revealed that COASY was up-regulated during normal erythroid differentiation, and its silencing prevented the formation of erythroid colonies, impeded erythroid differentiation, and precluded heme accumulation. In patients with MDS-RS, loss of protein due to COASY mis-splicing led to depletion of both CoA and succinyl-CoA. Supplementation with COASY substrate (vitamin B5) rescued CoA and succinyl-CoA concentrations in SF3B1mut cells and mended erythropoiesis differentiation defects in MDS-RS primary patient cells. Our findings reveal a key role of the COASY pathway in erythroid maturation and identify upstream and downstream metabolites of COASY as a potential treatment for anemia in patients with MDS-RS.

Design, Analysis, and 3D Printing of a Patient-Specific Polyetheretherketone Implant for the Reconstruction of Zygomatic Deformities.

The reconstruction of craniomaxillofacial deformities, especially zygomatic bone repair, can be exigent due to the complex anatomical structure and the sensitivity of the crucial organs involved. The need to reconstruct the zygomatic bone in the most precise way is of crucial importance for enhancing the patient outcomes and health care-related quality of life (HRQL). Autogenous bone grafts, despite being the gold standard, do not match bone forms, have limited donor sites and bone volume, and can induce substantial surgical site morbidity, which may lead to adverse outcomes. The goal of this study is to provide an integrated approach that includes various processes, from patient scanning to implant manufacture, for the restoration of zygomatic bone abnormalities utilizing Polyetheretherketone (PEEK) material, while retaining adequate aesthetic and facial symmetry. This study takes an integrated approach, including computer-aided implant design using the mirror reconstruction technique, investigating the biomechanical behavior of the implant under loading conditions, and carrying out a fitting accuracy analysis of the PEEK implant fabricated using state-of-the-art additive manufacturing technology. The findings of the biomechanical analysis results reveal the largest stress of approximately 0.89 MPa, which is relatively low in contrast to the material's yield strength and tensile strength. A high degree of sturdiness in the implant design is provided by the maximum value of strain and deformation, which is also relatively low at roughly 2.2 × 10-4 and 14 µm. This emphasizes the implant's capability for load resistance and safety under heavy loading. The 3D-printed PEEK implant observed a maximum deviation of 0.4810 mm in the outside direction, suggesting that the aesthetic result or the fitting precision is adequate. The 3D-printed PEEK implant has the potential to supplant the zygoma bone in cases of severe zygomatic reconstructive deformities, while improving the fit, stability, and strength of the implant.

Modeling Consequences of COVID-19 and Assessing Its Epidemiological Parameters: A System Dynamics Approach.

In 2020, coronavirus (COVID-19) was declared a global pandemic and it remains prevalent today. A necessity to model the transmission of the virus has emerged as a result of COVID-19's exceedingly contagious characteristics and its rapid propagation throughout the world. Assessing the incidence of infection could enable policymakers to identify measures to halt the pandemic and gauge the required capacity of healthcare centers. Therefore, modeling the susceptibility, exposure, infection, and recovery in relation to the COVID-19 pandemic is crucial for the adoption of interventions by regulatory authorities. Fundamental factors, such as the infection rate, mortality rate, and recovery rate, must be considered in order to accurately represent the behavior of the pandemic using mathematical models. The difficulty in creating a mathematical model is in identifying the real model variables. Parameters might vary significantly across models, which can result in variations in the simulation results because projections primarily rely on a particular dataset. The purpose of this work was to establish a susceptible-exposed-infected-recovered (SEIR) model describing the propagation of the COVID-19 outbreak throughout the Kingdom of Saudi Arabia (KSA). The goal of this study was to derive the essential COVID-19 epidemiological factors from actual data. System dynamics modeling and design of experiment approaches were used to determine the most appropriate combination of epidemiological parameters and the influence of COVID-19. This study investigates how epidemiological variables such as seasonal amplitude, social awareness impact, and waning time can be adapted to correctly estimate COVID-19 scenarios such as the number of infected persons on a daily basis in KSA. This model can also be utilized to ascertain how stress (or hospital capacity) affects the percentage of hospitalizations and the number of deaths. Additionally, the results of this study can be used to establish policies or strategies for monitoring or restricting COVID-19 in Saudi Arabia.

Self-Propelled Rotary Tools in Hard Turning: Analysis and Optimization via Finite Element Models.

This study investigates self-propelled rotary tool (SPRT) performance in hard turning using 3D finite element (FE) models. The FE models developed in this study are based on coupled temperature-displacement analysis using an explicit time-integration scheme. The developed FE models can predict chip morphology, cutting forces, tool and workpiece stresses and temperatures. For model verification, hard turning experiments were conducted using an SPRT on AISI 4340 bars. Cutting forces and maximum tool-chip interface temperatures were recorded and compared with the model findings. The effects of different process parameters were analyzed and discussed using the developed FE models. The FE models were run with a central composite design (CCD-25) matrix with four input variables, i.e., the cutting speed, the feed rate, the depth of the cut and the inclination angle. Response surfaces based on the Gaussian process were generated for each performance variable in order to predict design points not available in the original design of the experiment matrix. An optimization study was carried out to minimize tool stress and temperature while setting limits for the material removal rate (MRR) and specific cutting energy for the process. Optimized processes were found with moderate cutting speeds and feed rates and high depths of cut and inclination angles.

A Multi-Part Orientation Planning Schema for Fabrication of Non-Related Components Using Additive Manufacturing.

Additive manufacturing (AM) is a technique that progressively deposits material in layer-by-layer manner (or in additive fashion) for producing a three-dimensional (3D) object, starting from the computer-aided design (CAD) model. This approach allows for the printing of complicated shaped objects and is quickly gaining traction in the aerospace, medical implant, jewelry, footwear, automotive, and fashion industries. AM, which was formerly used for single part customization, is currently being considered for mass customization of parts because of its positive impacts. However, part quality and build time are two main impediments to the deployment of AM for mass production. The optimal part orientation is fundamental for maximizing the part's quality as well as being critical for reducing the fabrication time. This research provides a new method for multi-part AM production that improves quality while reducing overall build time. The automatic setup planning or orientation approach described in this paper employs two objective functions: the quality of the build component and the build time. To tackle the given problem, it introduces a three-step genetic algorithm (GA)-based solution. A feature-based technique is utilized to generate a collection of finite alternative orientations for each component within a specific part group to ensure each part's individual build quality. Then, a GA was utilized to find the best combination of part build orientations at a global optimal level to reduce material consumption and build time. A case study of orienting nine components concurrently inside a given building chamber was provided for illustration. The findings suggest that the developed technique can increase quality, reduce support waste, and shorten overall production time. When components are positioned optimally rather than in random orientations, build time and support volume are reduced by approximately 7% and 16%, respectively.

Process development and preclinical evaluation of a major Plasmodium falciparum blood stage vaccine candidate, Cysteine-Rich Protective Antigen (CyRPA).

Plasmodium falciparum Cysteine-Rich Protective Antigen (CyRPA) is an essential, highly conserved merozoite antigen that forms an important multi-protein complex (RH5/Ripr/CyRPA) necessary for erythrocyte invasion. CyRPA is a promising blood-stage vaccine target that has been shown to elicit potent strain-transcending parasite neutralizing antibodies. Recently, we demonstrated that naturally acquired immune anti-CyRPA antibodies are invasion-inhibitory and therefore a correlate of protection against malaria. Here, we describe a process for the large-scale production of tag-free CyRPA vaccine in E. coli and demonstrate its parasite neutralizing efficacy with commonly used adjuvants. CyRPA was purified from inclusion bodies using a one-step purification method with high purity (>90%). Biochemical and biophysical characterization showed that the purified tag-free CyRPA interacted with RH5, readily detected by a conformation-specific CyRPA monoclonal antibody and recognized by sera from malaria infected individuals thus indicating that the recombinant antigen was correctly folded and retained its native conformation. Tag-free CyRPA formulated with Freund's adjuvant elicited highly potent parasite neutralizing antibodies achieving inhibition of >90% across diverse parasite strains. Importantly, we identified tag-free CyRPA/Alhydrogel formulation as most effective in inducing a highly immunogenic antibody response that exhibited efficacious, cross-strain in vitro parasite neutralization achieving ~80% at 10 mg/ml. Further, CyRPA/Alhydrogel vaccine induced anti-parasite cytokine response in mice. In summary, our study provides a simple, scalable, cost-effective process for the production of tag-free CyRPA that in combination with human-compatible adjuvant induces efficacious humoral and cell-mediated immune response.

Tool Wear Prediction When Machining with Self-Propelled Rotary Tools.

The performance of a self-propelled rotary carbide tool when cutting hardened steel is evaluated in this study. Although various models for evaluating tool wear in traditional (fixed) tools have been introduced and deployed, there have been no efforts in the existing literature to predict the progression of tool wear while employing self-propelled rotary tools. The work-tool geometric relationship and the empirical function are used to build a flank wear model for self-propelled rotary cutting tools. Cutting experiments are conducted on AISI 4340 steel, which has a hardness of 54-56 HRC, at various cutting speeds and feeds. The rate of tool wear is measured at various intervals of time. The constant in the proposed model is obtained using genetic programming. When experimental and predicted flank wear are examined, the established model is found to be competent in estimating the rate of rotary tool flank wear progression.

Single cell analyses identify a highly regenerative and homogenous human CD34+ hematopoietic stem cell population.

The heterogeneous nature of human CD34+ hematopoietic stem cells (HSCs) has hampered our understanding of the cellular and molecular trajectories that HSCs navigate during lineage commitment. Using various platforms including single cell RNA-sequencing and extensive xenotransplantation, we have uncovered an uncharacterized human CD34+ HSC population. These CD34+EPCR+(CD38/CD45RA)- (simply as EPCR+) HSCs have a high repopulating and self-renewal abilities, reaching a stem cell frequency of ~1 in 3 cells, the highest described to date. Their unique transcriptomic wiring in which many gene modules associated with differentiated cell lineages confers their multilineage lineage output both in vivo and in vitro. At the single cell level, EPCR+ HSCs are the most transcriptomically and functionally homogenous human HSC population defined to date and can also be easily identified in post-natal tissues. Therefore, this EPCR+ population not only offers a high human HSC resolution but also a well-structured human hematopoietic hierarchical organization at the most primitive level.

Adaptive Mechanism for Designing a Personalized Cranial Implant and Its 3D Printing Using PEEK.

The rehabilitation of the skull's bones is a difficult process that poses a challenge to the surgical team. Due to the range of design methods and the availability of materials, the main concerns are the implant design and material selection. Mirror-image reconstruction is one of the widely used implant reconstruction techniques, but it is not a feasible option in asymmetrical regions. The ideal design approach and material should result in an implant outcome that is compact, easy to fit, resilient, and provides the perfect aesthetic and functional outcomes irrespective of the location. The design technique for the making of the personalized implant must be easy to use and independent of the defect's position on the skull. As a result, this article proposes a hybrid system that incorporates computer tomography acquisition, an adaptive design (or modeling) scheme, computational analysis, and accuracy assessment. The newly developed hybrid approach aims to obtain ideal cranial implants that are unique to each patient and defect. Polyetheretherketone (PEEK) is chosen to fabricate the implant because it is a viable alternative to titanium implants for personalized implants, and because it is simpler to use, lighter, and sturdy enough to shield the brain. The aesthetic result or the fitting accuracy is adequate, with a maximum deviation of 0.59 mm in the outside direction. The results of the biomechanical analysis demonstrate that the maximum Von Mises stress (8.15 MPa), Von Mises strain (0.002), and deformation (0.18 mm) are all extremely low, and the factor of safety is reasonably high, highlighting the implant's load resistance potential and safety under high loading. Moreover, the time it takes to develop an implant model for any cranial defect using the proposed modeling scheme is very fast, at around one hour. This study illustrates that the utilized 3D reconstruction method and PEEK material would minimize time-consuming alterations while also improving the implant's fit, stability, and strength.

Plasmodium falciparum Cysteine-Rich Protective Antigen (CyRPA) Elicits Detectable Levels of Invasion-Inhibitory Antibodies during Natural Infection in Humans.

Plasmodium falciparum cysteine-rich protective antigen (CyRPA) is a conserved component of an essential erythrocyte invasion complex (RH5/Ripr/CyRPA) and a target of potent cross-strain parasite-neutralizing antibodies. While naturally acquired human RH5 antibodies have been functionally characterized, there are no similar reports on CyRPA. Thus, we analyzed the parasite-neutralizing activity of naturally acquired human CyRPA antibodies. In this regard, CyRPA human antibodies were measured and purified from malaria-infected plasma obtained from patients in central India and analyzed for their parasite neutralizing activity via in vitro growth inhibition assays (GIA). We report that, despite being susceptible to antibodies, CyRPA is a highly conserved antigen that does not appear to be under substantial immune selection pressure, as a very low acquisition rate for anti-CyRPA antibodies was reported in malaria-exposed Indians. We demonstrate for the first time that the small amounts of natural CyRPA antibodies exhibited functional parasite-neutralizing activity and that a CyRPA-based vaccine formulation induces highly potent antibodies in rabbits. Importantly, the vaccine-induced CyRPA antibodies exhibited a robust 50% inhibitory concentration (IC50) of 21.96 µg/ml, which is comparable to the IC50 of antibodies against the leading blood-stage vaccine candidate, reticulocyte-binding-like homologous protein 5 (RH5). Our data support CyRPA as a unique vaccine target that is highly susceptible to immune attack but is highly conserved compared to other leading candidates such as MSP-1 and AMA-1, further substantiating its promise as a leading blood-stage vaccine candidate.

Friction Stir Welding of Thick Plates of 4Y3Gd Mg Alloy: An Investigation of Microstructure and Mechanical Properties.

Applications of non-ferrous light metal alloys are especially popular in the field of aerospace. Hence it is important to investigate their properties in joining processes such as welding. Solid state joining process such as friction stir welding (FSW) is quite efficient for joining non-ferrous alloys, but with thick plates, challenges increase. In this study, Mg alloy plates of thickness 11.5 mm were successfully welded via single-pass FSW. Due to the dynamic recrystallization, grain size in the stir zone was reduced to 16 µm which is ≈15 times smaller than the parent material. The optimized rotational speed and traverse speed for optimum weld integrity were found to be 710 rpm and 100 mm/min, respectively. A sound weld with 98.96% joint efficiency, having an Ultimate Tensile Strength (UTS) of 161.8 MPa and elongation of 27.83%, was accomplished. Microhardness of the nugget was increased by 14.3%.

Genetic disruption of Plasmodium falciparum Merozoite surface antigen 180 (PfMSA180) suggests an essential role during parasite egress from erythrocytes.

Plasmodium falciparum, the parasite responsible for severe malaria, develops within erythrocytes. Merozoite invasion and subsequent egress of intraerythrocytic parasites are essential for this erythrocytic cycle, parasite survival and pathogenesis. In the present study, we report the essential role of a novel protein, P. falciparum Merozoite Surface Antigen 180 (PfMSA180), which is conserved across Plasmodium species and recently shown to be associated with the P. vivax merozoite surface. Here, we studied MSA180 expression, processing, localization and function in P. falciparum blood stages. Initially we examined its role in invasion, a process mediated by multiple ligand-receptor interactions and an attractive step for targeting with inhibitory antibodies through the development of a malaria vaccine. Using antibodies specific for different regions of PfMSA180, together with a parasite containing a conditional pfmsa180-gene knockout generated using CRISPR/Cas9 and DiCre recombinase technology, we demonstrate that this protein is unlikely to play a crucial role in erythrocyte invasion. However, deletion of the pfmsa180 gene resulted in a severe egress defect, preventing schizont rupture and blocking the erythrocytic cycle. Our study highlights an essential role of PfMSA180 in parasite egress, which could be targeted through the development of a novel malaria intervention strategy.

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes.

Myelodysplastic syndrome (MDS) are clonal haematopoietic stem cell (HSC) disorders driven by a complex combination(s) of changes within the genome that result in heterogeneity in both clinical phenotype and disease outcomes. MDS is among the most common of the haematological cancers and its incidence markedly increases with age. Currently available treatments have limited success, with <5% of patients undergoing allogeneic HSC transplantation, a procedure that offers the only possible cure. Critical contributions of the bone marrow microenvironment to the MDS have recently been investigated. Although the better understanding of the underlying biology, particularly genetics of haematopoietic stem cells, has led to better disease and risk classification; however, the role that the bone marrow microenvironment plays in the development of MDS remains largely unclear. This review provides a comprehensive overview of the latest developments in understanding the aetiology of MDS, particularly focussing on understanding how HSCs and the surrounding immune/non-immune bone marrow niche interacts together.