Miracle-dz/UniFAR-FTUs huggingface dataset:
Dysregulated MicroRNA Expression and Chronic Lung Allograft Rejection in Recipients With Antibodies to Donor HLA

The pathogenesis of chronic rejection, Bronchiolitis Obliterans Syndrome (BOS) following lung transplantation (LT) is poorly understood. We hypothesized that development of antibodies to HLA (DSA) is associated with dysregulation of microRNA (miRNA) that predisposes BOS. Towards this, miRNA profiling of mononuclear cells from 10 stable LT (DSA−BOS−), 10 LT with DSA+BOS− (DSA group) and 10 LT with DSA+BOS+ (BOS group) were performed. Prediction by mirPath indicated that differential miRNAs in DSA+BOS− compared to stable are significantly up‐regulated (relative fold >2, p < 0.05) for TGF‐β and B cell receptor signal pathways. A total of seventy‐four miRNAs were up‐regulated and six miRNAs were down regulated in LT with DSA+BOS+ when compared to stable (relative fold >2, p < 0.05). There was also significant enrichment of cell cycle and gap junction pathways. An inverse correlation between expression of two key miRNAs and their target genes were observed: miR‐369‐5p and miR‐548d were down regulated in DSA+ LT while their gene targets in TGF‐β signal pathways were up‐regulated. In addition, miR‐628‐5p and miR‐134 were down regulated and their target genes (B cell development) were up‐regulated. Therefore, we conclude that alloimmunity induced changes in miRNAs affecting the TGF‐β and B cell receptor signal pathways play important roles in BOS development.
A technique combination approach to requirements engineering

An approach to requirements engineering based on a combination of early prototyping, scenario-based analysis and design rationale is described. Requirements are elicited by presenting users with a prototype-simulation of a prospective design, combined with rationale based techniques for structuring probe questions. Design of analysis sessions and a walkthrough method for requirements elicitation are reported in three layers for linking questions to artefact/scenario demonstrations, follow-up questioning for user-system dependencies and handling user-analyst discourse. An empirical study of the requirements analysis approach is reported. The study used a ship board emergency application. The technique combination approach proved very effective in eliciting requirements but differences in analyst style were an important variable. Recommendations are made for designing and managing requirements capture sessions using scenario-based approaches.
A Current-Sensitive Front-End Amplifier for Nano-Biosensors with a 2MHz BW

Active resistors up to 300GOmega operating down to the fA range are implemented in the feedback path of an integrator-differentiator transimpedance amplifier for high-sensitivity current measurements. The system has 4fA/radicHz noise up to 100kHz, a 2MHz bandwidth, and ensures unlimited measuring time even with nA DC input currents
STUDIES ON BACTERIEMIA

Intravenous injection of staphylococci produced a marked, transient granulocytopenia inrabbits. Leukopenia was rapidly followed by return of polymorphonuclear leukocytes to the peripheral blood, and normal circulating granulocyte levels were reestablished within 20 to 40 minutes. Differential arterio-venous leukocyte studies showed that polymorphonuclear leukocytes were trapped within the pulmonary vascular bed and, less constantly, in the splanchnic viscera during the initial 10 to 20 minutes following the injection of staphylococci. Granulocytes were subsequently found in larger numbers in blood leaving the lungs and splanchnic tissues, suggesting that entrapped polymorphonuclear leukocytes rapidly reentered the blood stream. This sequence of changes in circulating granulocytes was not significantly altered by splenectomy or the administration of cortisone. It has previously been shown that virtually all staphylococci in the blood stream are found within circulating polymorphonuclear leukocytes 10 to 40 minutes after the injection of culture (9). It is during this period that granulocytes return to the blood stream in large numbers. These observations suggest that staphylococci are phagocyted by polymorphonuclear leucocytes temporarily sequestered in the lungs and splanchnic viscera. It appears probable that some sequestered granulocytes containing living staphylococci subsequently return to the circulation. Such intraleukocytic staphylococci are believed to play a role in the maintenance of bacteriemia.
Calcium/calmodulin‐dependent protein kinase (CaMK) Iα mediates the macrophage inflammatory response to sepsis

Dysregulated Ca2+ handling is prevalent during sepsis and postulated to perpetuate the aberrant inflammation underlying subsequent organ dysfunction and death. The signal transduction cascades mediating these processes are unknown. Here, we identify that CaMKIα mediates the Mφ response to LPS in vitro and the inflammation and organ dysfunction of sepsis in vivo. We show that LPS induced active pThr177‐CaMKIα in RAW 264.7 cells and murine peritoneal Mφ, which if inhibited biochemically with STO609 (CaMKK inhibitor) or by RNAi, reduces LPS‐induced production of IL‐10. Transfection of constitutively active CaMKIα (CaMKI293), but not a kinase‐deficient mutant (CaMKI293K49A), induces IL‐10 release. This production of IL‐10 is mediated by CaMKIα‐dependent regulation of p38 MAPK activation. CaMKIα activity also mediates the cellular release of HMGB1 by colocalizing with and regulating the packaging of HMGB1 into secretory lysosomes. During endotoxemia, mice receiving in vivo CaMKIαRNAi display reduced systemic concentrations of IL‐10 and HMGB1 in comparison with mice receiving NTRNAi. These data support the biological relevance of CaMKIα‐dependent IL‐10 production and HMGB1 secretion. In a CLP model of sepsis, CaMKIαRNAi mice display reduced systemic concentrations of IL‐10, IL‐6, TNF‐α, and HMGB1 in comparison with NTRNAi mice, which correlate with reductions in the development of renal dysfunction. These data support that CaMKIα signaling is integral to the Mφ responding to LPS and may also be operant in vivo in regulating the inflammation and organ dysfunction consequent to sepsis.
The medical student global health experience: professionalism and ethical implications

Medical student and resident participation in global health experiences (GHEs) has significantly increased over the last decade. In response to growing student interest and the proven impact of such experiences on the education and career decisions of resident physicians, many medical schools have begun to establish programmes dedicated to global health education. For the innumerable benefits of GHEs, it is important to note that medical students have the potential to do more harm than good in these settings when they exceed their actual capabilities as physicians-in-training. While medical training programmes are beginning to provide students with the knowledge to put their GHEs in context, they must remember that they also bear the responsibility of training their students in a framework to approach these experiences in a principled and professional way. It is necessary that these institutions provide adequate and formalised preparation for both clinical and ethical challenges of working in resource-poor settings. This paper outlines potential benefits and risks of GHEs and delineates recommendations to some of the current issues.
Zum Knochenleitungshören Von Impulsen: Physikalische Messungen der Ausbreitungsgeschwindigkeit

Die Angaben des Schrifttums zur Ausbreitungsgeschwindigkeit von Knochenschall im menschlichen Schadel gehen auseinander. Sie reichen von 100–300 m/sec (Franke, Zwislocki) bis 3000 m/sec (Allen & Fernandez). —Die Abtastung der Schwingungen des von einzelnen Knochenschall-Im-pulsen angeregten Schadels mit einem beschleunigungsempfindlichen Wandler ohne fremden Bezugspunkt ergab, das sich sowohl der Kopf des Lebenden als auch das Schadelskelett wie ein anisotropes Medium verhalt: An verschiedenen Orten wurden verschiedene Ausbreitungsgeschwindig-keiten gemessen. Auf der Kalotte am niedrigsten (um 500 m/sec), nahmen sie zur Schadelbasis hin zu (bis 3000 m/sec). Fur den Weg zwischen beiden Felsenbeinen benotigten die Impulse etwa 100–200 μsec. Die erste Aus-lenkung des Beschleunigungsempfangers hatte unabhangig vom Ort stets die gleiche Phase. Demnach riefen diese Impulse nicht Translationsbe-wegungen des Schadelganzen hervor, sondern transversale “Wellen auf seiner Oberflache. ”
Tolerogenic dendritic cells: molecular and cellular mechanisms in transplantation

During the discovery of mechanisms that govern immune activation and suppression, immune tolerance always came second in the scientific timeline. This has subsequently shaped the advances in the clinical translation of DC therapy protocols used for immunostimulation or immunosuppression. With several hundred clinical trials already registered within the U.S. National Institutes of Health for the use of DCs in cancer vaccination, only a few involve TolDCs for use as negative vaccines. However, as a result of the strong scientific rationale from preclinical and clinical trials, the use of negative vaccination in organ transplantation is likely on its way to reach the extent of the use of positive cancer vaccines in the future. As the underlying mechanisms emerge, the role of DCs in the induction of transplant tolerance is recognized unambiguously as central in the bidirectional communication with various types of immune cells. This is achieved by a complex interplay of numerous tolerogenic signals involving regulatory cytokines and other surface‐bound or soluble inhibitory molecules associated with corresponding inhibitory signaling cascades. A detailed understanding of these processes will accelerate the advances of clinical immunologists in translating their knowledge from bench to bedside. In this review, we present the role of TolDCs as well as the most recent findings concerning associated molecular and cellular mechanisms that shape the balance between regulatory and effector immune responses during organ transplantation.
Selective blockade of lymphopoiesis induced by kalanchosine dimalate: inhibition of IL‐7‐dependent proliferation

Lymphopoiesis and myelopoiesis continuously generate mature cells from hematopoietic cell progenitors during the lifetime of the organism. The identification of new endogenous or exogenous substances that can act specifically on the differentiation of distinct cell lineages is of relevance and has potential therapeutical use. Kalanchoe brasiliensis (Kb) is a medicinal plant from the Crassulaceae family, used in folk medicine to treat inflammatory and infectious diseases. Here, we show that short‐term treatment of naïve mice with Kb led to a strong and selective inhibition of lymphopoiesis, affecting B and T cell lineages without reduction of the myeloid lineage development. Similar effects were observed after treatment with the highly purified compound kalanchosine dimalate (KMC), obtained from Kb. Numbers of mature lymphocytes in secondary lymphoid organs were preserved in Kb(KMC)‐treated mice. The effect of Kb(KMC) was not a result of secondary augmentation of plasma levels of endogenous corticoids; neither involves TNF‐α, type‐I IFN, or TLR2/TLR4 ligands, which have all been described as selective inhibitors of lymphopoiesis. Flow cytometry analysis of the phenotypes of T and B cell precursors indicate a blockade of maturation on IL‐7‐dependent, proliferative stages. In vitro, Kb(KMC) inhibited the IL‐7‐dependent proliferation of pre‐B cells and does not induce massive apoptosis of B and T cell precursors. These results suggest that Kb(KMC) is selectively blocking lymphopoiesis through a mechanism that does not involve the previously characterized substances, possibly acting on the IL‐7 signaling pathway, opening new perspectives for a potential therapeutic use of Kb‐derived drugs.
EBV‐Positive and EBV‐Negative Posttransplant Diffuse Large B Cell Lymphomas Have Distinct Genomic and Transcriptomic Features

The molecular pathogenesis of posttransplant diffuse large B cell lymphoma (PT‐DLBCL) is largely unknown. We have recently shown that Epstein‐Barr virus–positive (EBV+) and –negative (EBV−) PT‐DLBCL have distinct gene expression profiles, and the transcriptomic profile of EBV− PT‐DLBCL is similar to that of DLBCL in immunocompetent individuals (IC‐DLBCL). To validate these observations at the genomic level, we performed array–comparative genome hybridization (aCGH) analysis of 21 EBV+ PT‐DLBCL, 6 EBV− PT‐DLBCL, and 11 control IC‐DLBCL, and subsequently combined genomic and transcriptomic data. The analysis showed that EBV+ and EBV− PT‐DLBCL have distinct aCGH profiles and shared only one recurrent imbalance. EBV− PT‐DLBCL, however, displayed at least 10 aberrations recurrent in IC‐DLBCL, among which characteristic gain of 3/3q and 18q, and loss of 6q23/TNFAIP3 as well as 9p21/CDKN2A. The most prevalent aberration in EBV+ PT‐DLBCL was gain/amplification of 9p24.1 targeting PDCD1LG2/PDL2. Our data indicate that the FOXP1 oncogene and the tumor suppressor CDKNA2 implicated in EBV− DLBCL, do not play a critical role in the pathogenesis of EBV+ PT‐DLBCL. Altogether, genomic profiling of PT‐/IC‐DLBCL confirms that EBV− and EBV+ PT‐DLBCL are distinct entities, while EBV− PT‐DLBCL has features in common with IC‐DLBCL. These findings support the hypothesis that EBV− PT‐DLBCL are de novo lymphomas in transplant recipients.
Opinions of private medical practitioners in Bloemfontein, South Africa, regarding euthanasia of terminally ill patients

The aim of this study was to determine the opinions of private medical practitioners in Bloemfontein, South Africa, regarding euthanasia of terminally ill patients. This descriptive study was performed amongst a simple random sample of 100 of 230 private medical practitioners in Bloemfontein. Information was obtained through anonymous self-administered questionnaires. Written informed consent was obtained. 68 of the doctors selected completed the questionnaire. Only three refused participation because they were opposed to euthanasia. Respondents were mainly male (74.2%), married (91.9%) and Afrikaans-speaking (91.9%). More were specialists (53.2%) than general practitioners (46.8%). A smaller percentage (35.5%) would never consider euthanasia for themselves compared to for their patients (46.8%). The decision should be made by the patient (50%), the patient’s doctor with two colleagues (46.8%), close family (45.2%) or a special committee of specialists in ethics and medicine (37.1%). The majority (46.9%) indicated that euthanasia should be performed by an independent doctor trained in euthanasia, followed by the patient’s doctor (30.7%). Notification should mainly be given to a special committee (49.9%). Only 9.8% felt that no notification was necessary. There was strong opposition to prescribing of medication to let the patient die. Withdrawal of essential medical treatment to speed up death was the most acceptable method. Although the responding group was fairly homogeneous, responses varied widely, indicating the complexity of opinions.
The role of diacylglyceride generation by phospholipase D and phosphatidic acid phosphatase in the activation of 5‐lipoxygenase in polymorphonuclear leukocytes

Diacylglycerides (DAGs) such as 1‐oleoyl‐2‐acetyl‐sn‐glycerol (OAG) stimulate 5‐lipoxygenase (5‐LO) enzyme activity and function as agonists for human polymorphonuclear leukocytes (PMNL) to induce 5‐LO product synthesis. Here, we addressed the role of endogenous DAG generation in agonist‐induced 5‐LO activation in human PMNL. Preincubation of PMNL with the phospholipase D (PLD) inhibitor 1‐butanol potently suppressed 5‐LO product synthesis induced by the Ca2+ ionophore A23187 or thapsigargin (TG) and blocked A23187‐evoked translocation of 5‐LO from the cytosol to the nuclear membrane, analyzed by subcellular fractionation as well as by indirect immunofluorescence microscopy. Tertiary‐butanol, a rather poor inhibitor of PLD, caused only moderate suppression of 5‐LO and hardly inhibited 5‐LO translocation. Interestingly, 1‐butanol failed to inhibit 5‐LO product formation when PMNL were stimulated with OAG (30 μM). Moreover, coincubation of A23187‐ or TG‐stimulated PMNL with OAG reversed inhibition of 5‐LO product formation by 1‐butanol in a concentration‐dependent manner (EC50, ∼1 μM) and also restored 5‐LO translocation. In addition, inhibition of phosphatidic acid phosphatase (PA‐P) by propranolol or bromoenol lactone caused suppression of 5‐LO product formation and of translocation, which could be reversed by addition of exogenous OAG. Together, our data suggest that in agonist‐stimulated PMNL, the endogenous formation of DAGs via the PLD/PA‐P pathway determines 5‐LO activation.
A 43.7mW 96GHz PLL in 65nm CMOS

Advances in nanoscale CMOS technology have made it feasible to implement W-Band circuits in CMOS. Recently, CMOS implementation of high-frequency circuits for applications such as 77GHz anti-collision systems, 94GHz imaging systems, and 100Gb/s Ethernet transceivers has attracted a lot of attention. In high-speed wireless and wireline communication systems, PLLs are one of the key building blocks and are extensively used to generate a stable reference frequency/clock. In this paper, a 96GHz PLL, implemented in 65nm CMOS, is presented that targets W-band applications.
IFN‐α produced by human plasmacytoid dendritic cells enhances T cell‐dependent naïve B cell differentiation

The development and quality of a humoral immune response are largely influenced by the environment that supports the activation of naïve B cells. Human PDCs, through their unique capacity to produce high levels of IFN‐α, have been shown earlier to enhance B cell responses stimulated by selected TLR ligands. In this study, we investigated whether PDCs also promote B cell activation induced by Th cell interactions and BCR ligation. Sorted human naive CD19+ CD27– B cells were activated in vitro with anti‐Ig and irradiated CD4+ T cells. Under these conditions, the presence of supernatants from TLR‐stimulated PDCs increased B cell proliferation, the frequency of B cells that differentiated to CD27high CD38high cells, and secretion of IgM. Similar results were observed when the B cells were activated in the presence of purified IFN‐α. In contrast, supernatants from stimulated MDCs did not augment these functions. Also, IFN‐α treatment of B cells up‐regulated the expression of costimulatory molecule CD86 but not CD40, CD80, MHC class II, or CD25. Although direct IFN‐α exposure of T cells suppressed their proliferative capacity, IFN‐α treatment of B cells led to a small increase in their capacity to induce superantigen‐driven activation of autologous CD4+ T cells. In summary, PDCs, via their production of IFN‐α, may render B cells more responsive to T cell contact, which in turn, facilitates B cell proliferation and differentiation to antibody‐producing cells.
Easier Control of Late‐Onset Cytomegalovirus Disease Following Universal Prophylaxis Through an Early Antiviral Immune Response in Donor‐Positive, Recipient‐Negative Kidney Transplants

Universal prophylaxis for cytomegalovirus (CMV) prevention is viable but, compared with a preemptive strategy, leads to higher incidence of late‐onset disease (LOD) associated with poor patient and graft survival. The purpose of this study was to compare LOD with early onset disease (EOD), with a focus on the highest risk kidney transplant recipients (KTRs): CMV seronegative recipients transplanted from seropositive donors (D+R−). Since CMV control depends on both antiviral treatment and specific immune response, we also compared Vδ2‐negative (Vδ2neg) γδ T cell expansion involved in CMV infection resolution. EOD was defined as occurring <3 mo and LOD as occurring >3 mo after transplantation. Depending on the period, universal prophylaxis or preemptive treatment was used. Overall, 168 D+R− KTRs were included between 2003 and 2011. LOD was associated with a lower peak DNAemia (p = 0.04), fewer recurrences (odds ratio 0.16; 95% confidence interval 0.05–0.55; p = 0.01) and shorter anti‐CMV curative treatment (40 vs. 60 days, p < 0.0001). As a corollary, we found that Vδ2neg γδ T cell expansion was faster in LOD than in EOD (31 vs. 168 days after the beginning of CMV disease, p < 0.0001). In D+R− KTRs, universal prophylaxis is associated with more LOD, which had better infection management and a faster immune response. These results support the use of universal prophylaxis over a preemptive strategy and reappraise outcomes of LOD.
POWER7TM local clocking and clocked storage elements

The design of the clocked storage elements (CSEs) and associated local clocking circuitry is a critical consideration for modern microprocessor projects[1], and the POWER7™ chip[2], designed in a 45nm silicon-on-insulator (SOI) technology, was no exception. The digital logic contained over 2M CSEs, and the design of these elements had a major impact not only on the area, power, and performance of the chip, but also on the reliability, testability, and the ability to debug and optimize the hardware. This paper will focus on the special features added to the CSE design with these considerations in mind.
Immunostaining evidence for PI(4,5)P2 localization at the leading edge of chemoattractant‐stimulated HL‐60 cells

It is well known that in fMLP‐stimulated neutrophils, phosphatidyl inositol 3,4,5‐trisphosphate [PI(3,4,5)P3] localizes at the leading edge of the cells. However, no effort has been made to study the PI 4,5‐bisphosphate [PI(4,5)P2] distribution in these cells. In fact, it has been suggested that PI(4,5)P2 is unlikely to localize, as its basal level is orders of magnitude higher than that of PI(3,4,5)P3. We developed an optimized immunostaining protocol for studying the endogenous distribution of PI(4,5)P2 in neutrophil‐like HL‐60 cells. We show that PI(4,5)P2 localizes sharply at the leading edge with an intensity gradient similar to that for PI(3,4,5)P3. The enzymes for the production of PI(4,5)P2, namely, PI5KIα and PI5KIγ, were also found to localize at the leading edge, further supporting our finding that PI(4,5)P2 localizes at the leading edge. These results imply that complementary regulation of PI3K and phosphate and tensin homolog (PTEN) is not the sole or dominant mechanism of PI(3,4,5)P3 polarization in HL‐60 cells.
A 40nm 16-core 128-thread CMT SPARC SoC processor

This next generation of Chip Multithreaded (CMT) SPARC SoC processor, code named Rainbow Falls, doubles on-chip thread count over its predecessor the UltraSparc T2+. The chip offers high levels of integration and scalability with twice the number of cores, a larger L2 cache, and higher maximum I/O bandwidth, within the same power envelope. Sixteen 8-threaded enhanced SPARC cores (SPC) provide 128 threads in a single die, delivering the highest thread count for a general-purpose microprocessor. The new cache coherency further allows up to 4-way glueless systems with a total of 512 threads. Each core communicates with the unified 6MB L2 cache through a crossbar (CCX) delivering 461GB/s (Fig. 5.2.1). A gasket (CXG) is also introduced to manage the congestion and synchronization of the massive interconnect between the 16 cores and the crossbar. This facilitates a synchronized delay control between any core and any L2 bank for partial core product binning and testing.
The implementation of POWER7TM: A highly parallel and scalable multi-core high-end server processor

The next processor of the POWER ™ family, called POWER7™ is introduced. Eight quad-threaded cores are integrated together with two memory controllers and high-speed system links on a 567mm2 die, employing 1.2B transistors in 45nm CMOS SOI technology [4]. High on-chip performance and therefore bandwidth is achieved using 11 layers of low-к copper wiring and devices with enhanced dual-stress liners. The technology features deep trench [DT] capacitors that are used to build the 32MB embedded DRAM L3 based on a 0. 067µm2 DRAM cell. DT capacitors are used also to reduce on-chip voltage-island supply noise. Focusing on speed, the dual-supply ripple-domino SRAM concepts follows the schemes described elsewhere.