Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of alloreactive KIR2DS1+ NK cells in haploidentical hematopoietic stem cell transplantation

In allo‐HSCT, donor‐derived, ″alloreactive″ NK cells have been shown to play a crucial role in the treatment of acute leukemia, contributing to eradication of leukemic blasts (GvL effect) and to clearance of residual recipient DCs and T lymphocytes (thus, preventing GvHD and graft rejection, respectively). Such alloreactive NK cells do not express CD94/NKG2A but express inhibitory KIRs, specific for HLA class I allotypes, present in the donor but lacking in the recipient. This review is focused on the role of the activating KIR2DS1 receptor (specific for the C2‐epitope of HLA‐C) in haplo‐HSCT. Recent data indicate that KIR2DS1 expression in HSC donors may represent a remarkable advantage in alloreactive NK responses. This is a result of a substantial increase in the NK‐mediated capability to kill, not only recipientsˈ leukemic cells but also DCs and T cell blasts. The beneficial effects mediated by alloreactive KIR2DS1+ NK cells may occur after de novo expression of CCR7 upon interaction with allogeneic, KIR ligand‐mismatched CCR7+ cells. As a consequence, they can be redirected to LNs, where they can prevent priming of donor T cells and induction of GvHD. Finally, KIR2DS1 expression may also significantly amplify the size of the alloreactive NK cell subset by switching a subset of “not alloreactive” NK cells into potent alloreactive cells.
B cell receptor‐induced Ca2+ mobilization mediates F‐actin rearrangements and is indispensable for adhesion and spreading of B lymphocytes

B cells acquire membrane‐bound cognate antigens from the surface of the APCs by forming an IS, similar to that seen in T cells. Recognition of membrane‐bound antigens on the APCs initiates adhesion of B lymphocytes to the antigen‐tethered surface, which is followed by the formation of radial lamellipodia‐like structures, a process known as B cell spreading. The spreading response requires the rearrangement of the submembrane actin cytoskeleton and is regulated mainly via signals transmitted by the BCR. Here, we show that cytoplasmic calcium is a regulator of actin cytoskeleton dynamics in B lymphocytes. We find that BCR‐induced calcium mobilization is indispensible for adhesion and spreading of B cells and that PLCγ and CRAC‐mediated calcium mobilization are critical regulators of these processes. Measuring calcium and actin dynamics in live cells, we found that a generation of actin‐based membrane protrusion is strongly linked to the dynamics of a cytoplasmic‐free calcium level. Finally, we demonstrate that PLCγ and CRAC channels regulate the activity of actin‐severing protein cofilin, linking BCR‐induced calcium signaling to the actin dynamics.
The integrated specification and analysis of functional, temporal, and resource requirements

The Graphical Communicating Shared Resources, GCSR, is a specification language with a precise, operational semantics for the specification and analysis of real-time systems. GCSR allows a designer to integrate the functional and temporal requirements of a real-time system along with its run-time resource requirements. The integration is orthogonal in the sense that it produces system models that are easy to modify, e.g., to reflect different resource requirements, allocations and scheduling disciplines. In addition, it renders the verification of resource related requirements natural and straightforward. The formal semantics of GCSR allows the simulation of a system model and the thorough verification of system requirements through equivalence checking and state space exploration. This paper reviews GCSR and reports our experience with the production cell case study.
Oxidative Stress and Antioxidant Supplementation in the Management of Diabetic Cardiovascular Disease

The diabetic state confers an increased propensity to accelerated atherogenesis. In addition to the established risk factors, there is evidence for increased oxidative stress in diabetes. Increased oxidative stress is manifested by increased lipid peroxidation, increased F2-isoprostanes, increased nitrotyrosine, and increased DNA damage. Also, in diabetics, there is increased superoxide release. With regard to diabetes, antioxidants such as α-tocopherol, α-lipoate, and ascorbic acid supplementation have been shown to be beneficial. Most importantly, α-tocopherol therapy, especially at high doses, clearly shows a benefit with regard to low-density lipoprotein oxidation, isoprostanes, and monocyte superoxide release. Thus, it appears that, in diabetes, antioxidant therapy could alleviate the increased attendant oxidative stress and emerge as an additional therapeutic modality.
Mibefradil suppresses the proliferation of pulmonary artery smooth muscle cells

Intracellular Ca2+ levels play a critical role in the regulation of vasodilation and vasoconstriction by stimulating pulmonary artery smooth muscle cell (PASMC) proliferation, which is important in the pathogenesis of pulmonary arterial hypertension (PAH); however, L-type Ca2+ channel antagonists are useful in only few patients with PAH. The present study sought to assess the effect of mibefradil, which blocks T-type Ca2+ channels, on PASMC proliferation and Ca2+ channel profile. Human PASMCs were stimulated with 25 ng/mL platelet-derived growth factor-BB (PDGF-BB) with and without 10 µM mibefradil or 100 nM sildenafil. After 48 or 72 h, PASMC proliferation and Ca2+ channel expression were assessed by MTT assays and western blot analysis, respectively. PDGF-BB-induced PASMC proliferation at 72 h (p<0.01), which was inhibited by both sildenafil and mibefradil (p<0.01). Transient receptor potential Ca2+ channel 6 (TRPC6) expression was significantly increased with PDGF-BB stimulation (p=0.009); however, no changes in TRPC1, TRPC3, CAV1.2, and CAV3.2 levels were observed. Although both TRPC1 and CAV1.2 expression levels were increased in PDGF-stimulated PASMCs on mibefradil and sildenafil treatment, it was not statistically significant (p=0.086 and 1.000, respectively). Mibefradil inhibits PDGF-BB-stimulated PASMC proliferation; however, the mechanism through which it functions remains to be determined. Further studies are required to elucidate the full therapeutic value of mibefradil for PAH.
Transient β‐catenin stabilization modifies lineage output from human thymic CD34+CD1a– progenitors

Increasing evidence includes Wnt proteins inside the group of master‐signaling pathways that govern immune and nonimmune differentiation systems, fundamental for normal development and homeostasis. Although their precise functions in bone marrow and thymus are still controversial, numerous studies have shown that Wnt signaling is able to control the proliferation of hematopoietic stem cells and thymic progenitors and might also affect their cell‐fate decisions and subsequent maturation. In the present work, we analyze the effect of transient stimulation of the canonical Wnt pathway in the differentiation potential of Lin–CD34+ CD1a– human thymic progenitors, a multipotent and heterogeneous cell population that has the capacity to develop into T cells, NK cells, monocytes, cDC, and pDC. Our results demonstrate that giving a boost to canonical Wnt signaling, triggered by transient exposure to Wnt3a or LiCl, the differentiation capacity of thymic progenitors changes, enhancing NK cell production. On the contrary, Wnt3a‐ or LiCl‐pretreated thymic progenitors generate a significantly lower number of myeloid lineage cells, monocytes, and cDC and exhibit a reduced capacity to differentiate into pDC lineage. As a possible mechanism for this effect, we show that Wnt3a‐ and LiCl‐pretreated progenitors change their membrane levels of receptors for cytokines pivotal for their expansion and differentiation, such as Flt3L. Moreover, canonical Wnt pathway stimulation modifies the transcription factor profile of CD34+CD1– thymocytes, increasing Hes‐1 and ID3 expression levels.
A group IIA‐secreted phospholipase A2 from snake venom induces lipid body formation in macrophages: the roles of intracellular phospholipases A2 and distinct signaling pathways

We investigated the ability of the sPLA2, known as MT‐III, isolated from the viperid snake Bothrops asper, to induce LB formation in macrophages and the major cellular signaling pathways involved in this process. The effects of MT‐III on ADRP localization and expression and macrophage ultrastructure were assessed. Our results showed that this sPLA2 induced a marked increase in LB numbers in macrophages, induced the recruitment of ADRP in macrophages, and up‐regulated ADRP expression. Ultrastructural analysis showed the presence of weakly and strongly osmiophilic LBs in sPLA2‐stimulated cells. Enlargement of the ER and Golgi cisterns was also observed. Pretreatment of cells with H7 or staurosporine (PKC inhibitors), LY294002 or wortmannin (PI3K inhibitors), SB202190 or PD98059 (p38MAPK and ERK1/2 inhibitors, respectively), or Pyr‐2 or Bel (cPLA2 and iPLA2 inhibitors, respectively) significantly reduced sPLA2‐induced LB formation. Herbimycin (a PTK inhibitor) and indomethacin or etoricoxib (COX inhibitors) failed to alter sPLA2‐induced effects. In conclusion, our results show for the first time the ability of a venom sPLA2 to induce the formation of LBs and the expression of ADRP in macrophages. Venom PLA2‐induced LB formation is dependent on PKC, PI3K, p38MAPK, ERK1/2, cPLA2, and iPLA2 signaling pathways but not on PTK, COX‐1, or COX‐2 pathways. Activation of the ER and Golgi complex may play an important role in the formation of LBs induced by this sPLA2 in macrophages.
A 14b 40MS/s Redundant SAR ADC with 480MHz Clock in 0.13pm CMOS

A 2-channel time-interleaved 40MS/s SAR ADC with redundancy is presented. The 0.13mum 1.5V CMOS design runs at 480MHz iteration clock and features 89dB THD and 81dB SNDR. Including the PLL, the second-order anti-alias filter, and reference buffer, the chip consumes 66mW and occupies 0.55mm2.
The claim for patient choice and equity

Recently, commentators close to and within the UK government have claimed that patient choice can increase equity in the context of the National Health Service. This article critically examines the basis for this claim through analysis of recent speeches and publications authored by secretaries of state for health and their policy advisers. It is concluded that this claim has not developed prospectively from an analysis of the causes of healthcare inequity, or even with a consistent normative definition of equity. The limited justification that is “framed in causal explanations” of inequity has suffered from an apparent disregard of the available evidence.
Adenosine A2A receptor activation limits graft‐versus‐host disease after allogenic hematopoietic stem cell transplantation

GVHD is a major barrier to broader use of allogenic HSCT for nonmalignancy clinical applications such as the treatment of primary immunodeficiencies and hemoglobinopathies. We show in a murine model of C57BL/6J (H2‐kb) → B6D2F1/J (H2‐kb/d) acute GVHD that when initiated 2 days before transplant, the activation of the adenosine A2AR with the selective agonist ATL146e inhibits the weight loss and mortality associated with disease progression. Furthermore, circulating levels of proinflammatory cytokines and chemokines, including IFN‐γ, IL‐6, CCL2, KC, and G‐CSF, are reduced significantly by 14‐day ATL146e treatment. The up‐regulation of CD25, CD69, and CD40L expression by donor CD4+ and CD8+ T cells is inhibited by A2AR activation; fewer CD3+ T cells are found in the liver, skin, and colon of ATL146e‐treated mice as compared with vehicle‐treated controls; and associated tissue injury is lessened. The delayed administration of ATL146e, beginning 9 days after HSCT, reverses GVHD‐associated body weight loss successfully, and improvement is sustained for the duration of treatment. We conclude that the selective activation of the A2AR has therapeutic potential in the prevention and treatment of acute GVHD.
A Review of Thermoplastic Ankle‐Foot Orthoses Adjustments/Replacements in Young Cerebral Palsy and Spina Bifida Patients

ABSTRACT A retrospective study was performed to determine how long a thermoplastic ankle-foot orthosis (AFO) will fit appropriately and when subsequent adjustment and replacement are indicated. Clinical records of cerebral palsy and spina bifida patients ages birth to 21 years who used six types of thermoplastic AFOs from 1982 to 1992 were reviewed. Neuromusculoskeletal functional status appears to determine the AFO design prescribed and its replacement. Adjustments to thermoplastic AFOs primarily involve heat flaring to alter plastic contours and provide sufficient space for donning, doffing and pressure relief over regions of bony prominence. Further research is necessary to confirm the results obtained in this study.
Practical Ophthalmology—a Manual for Beginning Residents

Practical Ophthalmology—a Manual for Beginning Residents . By Fred M Wilson II. Pp 415. £27 (Members of BMA and AAO £25.) San Francisco: American Academy of Ophthalmology, 1996. ISBN 15 605 50341. This book is aimed at the trainee ophthalmologist starting his first post in ophthalmology who has a steep learning curve with much new information and new skills to acquire. The intention is that the reader should learn good clinical practice from the start. The reader may wish to use the book as reading before clinical contact, but also as a reference manual to allow the correct performance of simple tasks. The introduction expounds not only the virtues of ophthalmology itself, but also the virtues expected of the trainee during his apprenticeship and later in his career, and the responsibilities, stresses, and ethics incumbent upon this. The duty of the trainee for continuing education is also underlined. The process of history taking and …
Myeloperoxidase associated with neutrophil extracellular traps is active and mediates bacterial killing in the presence of hydrogen peroxide

A variety of inflammatory stimuli induces NETs. These structures consist of a network of chromatin strands associated with predominately granule proteins, including MPO. NETs exhibit antimicrobial activity, which is proposed to augment the more‐established mechanism of phagosomal killing. They may also be detrimental to the host in situations such as chronic inflammation or severe sepsis. The objective of this study was to establish whether MPO associated with NETs is active and able to kill bacteria. Neutrophils were stimulated with PMA to release NETs. Peroxidase activity measurements were performed and showed that enzymatically active MPO was released from the neutrophils, 2–4 h after stimulation, concomitant with NET formation. Approximately 30% of the total cellular MPO was released, with the majority bound to the NETs. The bound enzyme retained its activity. Staphylococcus aureus were not killed when added to preformed NETs under our assay conditions. However, addition of H2O2 to the bacteria in the presence of NETs resulted in MPO‐dependent killing, which was observed with NETs in situ and with NETs when they were removed from the neutrophils by limited DNase digestion. Our results show that the enzymatic activity of MPO on NETs could contribute to antimicrobial activity or tissue injury when NETs are released from neutrophils at sites of infection or inflammation.
Switching from Tacrolimus to Cyclosporine for Cholestatic Hepatitis due to Hepatitis C Virus Reinfection after Liver Transplantation

Recurrence of hepatitis C virus (HCV) infection after liver transplantation has been shown to negatively affect graft and patient survival. Combination therapy with pegylated interferon (PEG-IFN) and ribavirin is efficacious, but poorly tolerated. A 57-year-old man with HCV infection and cirrhosis underwent cadaveric liver transplantation in the United States. The HCV genotype was 1b. The immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil, and prednisolone. Liver function was stable until 4 months after transplantation, but then deteriorated, accompanied by a rapid rise in the serum HCV-RNA level. Liver biopsy revealed the recurrence of HCV infection, and treatment with PEG-IFN alpha-2b plus ribavirin was initiated. The patient responded well to therapy, and liver function improved, but high HCV-RNA levels persisted. On postoperative day 260, the patient had a relapse of hepatitis and received β-interferon 3 MU/day for 2 consecutive weeks. The patient responded well, but only transie.
Niet-tuberculeuze mycobacteriële lymfadenitis

A 4-year-old girl was referred with a chronically enlarged left cervical lymphadenitis of the neck. This swelling appeared to be caused by a Mycobacterium avium infection. Mycobacterium avium belongs to the group of nontuberculous mycobacteria. These micro-organisms can cause a cervicofacial lymphadenitis in children in the head and neck region. The children are healthy, and are seen to have a submandibular or preauricular swelling. Early recognition of the disease is important because it gives the best chance that treatment will result in a successful outcome.
A chopper current-feedback instrumentation amplifier with a 1mHz 1/ƒ noise corner and an AC-coupled ripple-reduction loop

In the precision mechatronics of wafer steppers, thermal expansion is an important source of error. To compensate for this, the temperature of critical mechanical components must be measured with high resolution (≪1µK), typically by using precision thermistor bridges. Furthermore, this resolution must be maintained over several minutes, which means that the amplifier used for bridge readout should have a 1/ƒ noise corner of only a few mHz. Such noise performance is well beyond the capabilities of currently available CMOS amplifiers [1–3].
Assessment of parental decision-making in neonatal cardiac research: a pilot study

Objective To assess parental permission for a neonate's research participation using the MacArthur competence assessment tool for clinical research (MacCAT-CR), specifically testing the components of understanding, appreciation, reasoning and choice. Study Design Quantitative interviews using study-specific MacCAT-CR tools. Hypothesis Parents of critically ill newborns would produce comparable MacCAT-CR scores to healthy adult controls despite the emotional stress of an infant with critical heart disease or the urgency of surgery. Parents of infants diagnosed prenatally would have higher MacCAT-CR scores than parents of infants diagnosed postnatally. There would be no difference in MacCAT-CR scores between parents with respect to gender or whether they did or did not permit research participation. Participants Parents of neonates undergoing cardiac surgery who had made decisions about research participation before their neonate's surgery. Methods The MacCAT-CR. Results 35 parents (18 mothers; 17 fathers) of 24 neonates completed 55 interviews for one or more of three studies. Total scores: magnetic resonance imaging (mean 36.6, SD 7.71), genetics (mean 38.8, SD 3.44), heart rate variability (mean 37.7, SD 3.30). Parents generally scored higher than published subject populations and were comparable to published control populations with some exceptions. Conclusions The MacCAT-CR can be used to assess parental permission for neonatal research participation. Despite the stress of a critically ill neonate requiring surgery, parents were able to understand study-specific information and make informed decisions to permit their neonate's participation.
PDE4 inhibition drives resolution of neutrophilic inflammation by inducing apoptosis in a PKA‐PI3K/Akt‐dependent and NF‐κB‐independent manner

PDE4 inhibitors are effective anti‐inflammatory drugs whose effects and putative mechanisms on resolution of inflammation and neutrophil apoptosis in vivo are still unclear. Here, we examined the effects of specific PDE4 inhibition on the resolution of neutrophilic inflammation in the pleural cavity of LPS‐challenged mice. LPS induced neutrophil recruitment that was increased at 4 h, peaked at 8–24 h, and declined thereafter. Such an event in the pleural cavity was preceded by increased levels of KC and MIP‐2 at 1 and 2 h. Treatment with the PDE4 inhibitor rolipram, at 4 h after LPS administration, decreased the number of neutrophils and increased the percentage of apoptotic cells in the pleural cavity in a PKA‐dependent manner. Conversely, delayed treatment with a CXCR2 antagonist failed to prevent neutrophil recruitment. Forskolin and db‐cAMP also decreased the number of neutrophils and increased apoptosis in the pleural cavity. The proapoptotic effect of rolipram was associated with decreased levels of the prosurvival protein Mcl‐1 and increased caspase‐3 cleavage. The pan‐caspase inhibitor zVAD‐fmk prevented rolipram‐induced resolution of inflammation. LPS resulted in a time‐dependent activation of Akt, which was blocked by treatment with rolipram or PI3K and Akt inhibitors, and PI3K and Akt inhibitors also enhanced apoptosis and promoted neutrophil clearance. Although LPS induced NF‐κB activation, which was blocked by rolipram, NF‐κB inhibitors did not promote resolution of neutrophil accumulation in this model. In conclusion, our data show that PDE4 inhibition resolves neutrophilic inflammation by promoting caspase‐dependent apoptosis of inflammatory cells by targeting a PKA/PI3K/Akt‐dependent survival pathway.
Digitally assisted quasi-V2 hysteretic buck converter with fixed frequency and without using large-ESR capacitor

The rapid advancement of processor technology has posed stringent challenges on power supply design. For high efficiency, switching converters are used. Frequent load switching requires the converters to have fast load transient response with recovery times in the order of µs, and therefore the switching frequency in the MHz range [1]. The transient overshoot and undershoot voltages must be within 10% of the output voltage, and such specifications are difficult to meet for a processor core voltage of 0.8V. For fast load transient, inductor current should be fed forward to the PWM generator, which needs a high performance integrated current sensor. In the output feedforward (or V2) converter, inductor current is sensed by the equivalent series resistor (ESR) of the output capacitor instead. The generic implementation of a V2 buck converter is shown in Fig. 26.3. 1 [2,3]. The output voltage, Vo, is fed back to the error-correction path (ECP) for precision output voltage control, and Vo is also directly fed to the PWM generator through the feedforward path (FFP). It is shown that the output voltage ripple, ΔVo, is dominated by ΔIℓ×RESR, and any change in Vo requires the PWM generator to adjust the inductor current immediately, thus speeding up the response. However, to make sure that the V2 converter operates properly without pulse skipping, a large ESR is needed. To eliminate a large ESR, a derivative-output-voltage (DOV) technique is suggested in [3] to extract the inductor current ripple through differentiating Vo. However, Vo is a noisy node and is affected by frequent load changes, and therefore obtaining accurate current information is challenging.
A 3MHz-BW 3.6GHz digital fractional-N PLL with sub-gate-delay TDC, phase-interpolation divider, and digital mismatch cancellation

Digital Fractional-N PLLs allows easy cancellation of ΔΣ quantization noise and spurs [1], [2]. However, the actual results depend dramatically on the linearity of the time-to-digital converter (TDC). This paper presents a 3MHz bandwidth fractional-N synthesizer, which combines a 4ps TDC with digital linearization algorithm and a feedback phase interpolator with mismatch cancellation algorithm. In contrast to other TDC linearization approaches [3], this structure allows multiplier-free computations, fast and accurate spur cancellation, as well as digital post-cancellation of phase errors induced by the phase interpolator mismatches, avoiding more complex calibration loops [4].