Alternative platelet differentiation pathways initiated by nonhierarchically related hematopoietic stem cells

Rare multipotent stem cells replenish millions of blood cells per second through a time-consuming process, passing through multiple stages of increasingly lineage-restricted progenitors. Although insults to the blood-forming system highlight the need for more rapid blood replenishment from stem cells, established models of hematopoiesis implicate only one mandatory differentiation pathway for each blood cell lineage. Here, we establish a nonhierarchical relationship between distinct stem cells that replenish all blood cell lineages and stem cells that replenish almost exclusively platelets, a lineage essential for hemostasis and with important roles in both the innate and adaptive immune systems. These distinct stem cells use cellularly, molecularly and functionally separate pathways for the replenishment of molecularly distinct megakaryocyte-restricted progenitors: a slower steady-state multipotent pathway and a fast-track emergency-activated platelet-restricted pathway. These findings provide a framework for enhancing platelet replenishment in settings in which slow recovery of platelets remains a major clinical challenge.Jacobsen and colleagues elucidate the nonhierarchical relationship between two types of stem cells: Vwf - hematopoietic stem cells that stably replenish all blood cell lineages without a platelet bias, and Vwf + stem cells that replenish almost exclusively platelets, and demonstrate that the two types utilize cellularly and molecularly distinct progenitor trajectories for replenishment of platelets

Human Bone Marrow Organoids for Disease Modeling, Discovery, and Validation of Therapeutic Targets in Hematologic Malignancies

A lack of models that recapitulate the complexity of human bone marrow has hampered mechanistic studies of normal and malignant hematopoiesis and the validation of novel therapies. Here, we describe a step-wise, directed-differentiation protocol in which organoids are generated from induced pluripotent stem cells committed to mesenchymal, endothelial, and hematopoietic lineages. These 3D structures capture key features of human bone marrow— stroma, lumen-forming sinusoids, and myeloid cells including proplatelet-forming megakaryocytes. The organoids supported the engraftment and survival of cells from patients with blood malignancies, including cancer types notoriously difficult to maintain ex vivo. Fibrosis of the organoid occurred following TGFβ stimulation and engraftment with myelofibrosis but not healthy donor–derived cells, validating this platform as a powerful tool for studies of malignant cells and their interactions within a human bone marrow–like milieu. This enabling technology is likely to accelerate the discovery and prioritization of novel targets for bone marrow disorders and blood cancers. SIGNIFICANCE: We present a human bone marrow organoid that supports the growth of primary cells from patients with myeloid and lymphoid blood cancers. This model allows for mechanistic studies of blood cancers in the context of their microenvironment and provides a much-needed ex vivo tool for the prioritization of new therapeutics.</p

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

The polymorphism of cytochrome P450 CYP2C19 and resistance to clopidogrel.

The purpose of this study is to investigate the role of CYP2C19 polymorphism on the incidence of adverse cardiovascular events in patients treated with clopidogrel and detection of potential prognostic factors predictive of resistance factors to clopidogrel have not been clearly elucidated

Surgery for colorectal cancer in the small town of Komotini

Christos Simoglou, Eirini Gymnopoulou, Lambros Simoglou, Marina Gymnopoulou, Konstantinia Nikolaou, Dimitrios GymnopoulosSurgical Clinic, S&amp;iota;smanogleio General Hospital, Komotini, GreeceBackground: Here we report our experience in treating colon cancer in the 5 years from 200 to 2011. Our surgical clinic treated 49 patients with colorectal cancer, of whom 28 (57.14%) were men of mean age 62 years and 21 (42.86%) were women of mean age 66 years.Methods: In 15 cases, the cancer was related to the rectum (30.61%) and the remaining 34 cases (69.39%) were related to the colon. We found synchronous cancer in two patients. One was found in the blank and the upper right while the second was found in the transverse and sigmoid colon. Six of our patients suffered from coexisting biliary lithiasis and underwent simultaneous cholecystectomy, and simultaneous bile duct exploration for common bile duct lithiasis was performed in one of these patients.Results: Twenty-eight of the patients with colon cancer were treated surgically on an emergency basis. There were two postoperative deaths due to septic shock and multiple organ failure. In total, we noted seven complications, all of which involved patients who had undergone emergency surgery. The length of hospital stay was 8&amp;ndash;14 days. Four patients with stage IV disease died 2 years after surgery, and the remainder are still alive.Conclusion: We conclude that colon cancer still occurs after the sixth decade, with a male predominance, and is mainly located in the rectum and sigmoid colon. The high rate of ileus in our region indicates inadequate diagnostic access for the residents of our region. However, mortality remains low.Keywords: anastomosis, colorectal cancer, Hartmann, colectomy, sigmoidectom

RADPlace-MS: A Timing-Driven Placer and Optimiser for ASICs Radiation Hardening

The manufacturing of modern Integrated Circuits (ICs), resistant against faults caused by ionising radiation, has become quite challenging due to the rapid advancement of VLSI technology. Additionally, the Radiation Hardening process, which involves making electronic cells and circuits resistant to damage or faults induced by ionising radiation, deviates from the conventional design flow. Thus, it generally suffers from insufficient support from industrial EDA tools. RADPlace is an academic timing-driven detailed placement algorithm that ensures spacing constraints among TMR triplet members. However, RADPlace, considering only the top critical paths of the circuit, limits the improvement in circuit timing, especially Total Negative Slack (TNS). In this work, we propose an improved RADPlace version (RADPlace-I) and a Multi-Step RADPlace version (RADPlace-MS), separating timing-driven optimisations from the placement step. Experimental results indicate that RADPlace-I achieves an average 21% improvement in Worst Negative Slack (WNS), while it achieves TNS improvement in most cases. On the other hand, RADPlace-MS achieves an average 54% and 45% improvement in WNS and TNS, respectively, compared to the original RADPlace version, with negligible impact on circuit total area and power. © 2022 IEEE

Timing errors in sta-based gate-level simulation

In this paper, we demonstrate that conventional STA-based, functional, gate-level simulation of asynchronous circuits with cycles is only as accurate as the STA engine used. This is, firstly because cycle cuts create local slew errors at cutpoints, and secondly because slew propagation may not be upper-bounded across multiple cut points in the same cycle. The use of an ASTA engine, which does not cut cycles, and properly bounds slews across cycles is a possible solution, which can indeed serve as an upper bound over SPICE, transistor level similations. We contrast STA and ASTA-based SDF-Annotated gate-level simulation results, with transistor level SPICE results, and demonstrate the impact of timing errors. © 2020 IEEE

Static Timing Analysis Induced Simulation Errors for Asynchronous Circuits

In this paper, we demonstrate that conventional Static Timing Anaysis (STA) based, functional, gate-level simulation of asynchronous circuits with cycles is only as accurate as the STA engine used. This is, firstly because cycle cuts create local slew errors at cutpoints, and secondly because slew propagation may not be upper bounded across multiple cut points in the same cycle. The use of an Asynchronous STA (ASTA) engine, which does not cut cycles, and properly bounds slews across cycles is a possible solution, which can indeed serve as an upper bound over SPICE transistor level similations. We contrast STA and ASTA-based gate-level simulations with transistor level SPICE simulations to demonstrate the impact of timing errors for 12 asynchronous control circuits, implemented by the Petrify tool, in a 0.25µm technology library. We show that STA-based simulation results are incorrectly more optimistic than ASTA, and it is possible for the simulation period to even be faster than SPICE, which is a major timing error. © 2021 IEE

Abax: 2D/3D legaliser supporting look-ahead legalisation and blockage strategies

Abax is a modern version of the classical Abacus, minimum displacement, greedy legaliser. Abax supports single-tier 2D or 3D legalisation for multiple, logic-on-logic 3D-IC tiers, efficient look-ahead legalisation of intermediate Global Placement (GP) iterations, Hard Macros, Blockages, row density constraints and multiple local cell displacement functions and cell orderings. For 3D-IC, Abax can produce multi-tier 3D-IC placements by performing Legalisation-based Partitioning. For efficient Look-ahead Legalisation, Abax supports two new local displacement cost functions, multi-cell mean and multi-cell total. We show that the classical single-cell displacement and multi-cell total can result in artifacts when legalising early intermediate GPs, and that multi-cell mean is the best candidate for Look-ahead Legalisation. Obstructions, i.e. Hard Macros and Blockages are handled by using two strategies. We present legalisation results for the ISPD2014 and ISPD2015 benchmarks, by using GP generated from Eh?Placer, and HPWL measurement by using RippleDP. For 3D, two-tier legalisation we illustrate a ∼30% reduction in HPWL for a set of ISPD2014 benchmarks. For 2D legalisation on the ISPD2015 benchmarks, our average HPWL increase over GP is 3.03%, compared to 7.21% of the Eh?Placer legaliser, and 43.16% of the RippleDP legaliser. © 2018 EDAA