Miracle-dz/UniFAR-FTUs huggingface dataset:
Inflammation Causes Resistance to Anti‐CD20–Mediated B Cell Depletion

B cells play a central role in antibody‐mediated rejection and certain autoimmune diseases. However, B cell–targeted therapy such as anti‐CD20 B cell–depleting antibody (aCD20) has yielded mixed results in improving outcomes. In this study, we investigated whether an accelerated B cell reconstitution leading to aCD20 depletion resistance could account for these discrepancies. Using a transplantation model, we found that antigen‐independent inflammation, likely through toll‐like receptor (TLR) signaling, was sufficient to mitigate B cell depletion. Secondary lymphoid organs had a quicker recovery of B cells when compared to peripheral blood. Inflammation altered the pharmacokinetics (PK) and pharmacodynamics (PD) of aCD20 therapy by shortening drug half‐life and accelerating the reconstitution of the peripheral B cell pool by bone marrow–derived B cell precursors. IVIG (intravenous immunoglobulin) coadministration also shortened aCD20 drug half‐life and led to accelerated B cell recovery. Repeated aCD20 dosing restored B cell depletion and delayed allograft rejection, especially B cell–dependent, antibody‐independent allograft rejection. These data demonstrate the importance of further clinical studies of the PK/PD of monoclonal antibody treatment in inflammatory conditions. The data also highlight the disconnect between B cell depletion on peripheral blood compared to secondary lymphoid organs, the deleterious effect of IVIG when given with aCD20 and the relevance of redosing of aCD20 for effective B cell depletion in alloimmunity.
A full-duplex 10GBase-T transmitter hybrid with SFDR >65dBc Over 1 to 400MHz in 40nm CMOS

A transmitter and echo cancellation hybrid for IEEE 802.3an 10GBase-T Ethernet standard is presented, that utilizes DSP techniques to enhance the linear cancellation, and analog non-linearity cancellation to eliminate the need of a high linearity transmitter. Implemented in 40nm CMOS, the transmitter has a residual distortion < −65dBc and residual linear echo < −30dBc over a bandwidth of 1 to 400MHz. The transmitter, including the echo-cancellation circuitry and on-chip DSP engine, consumes 250mW power and occupies 0.9mm2.
A 7MB/s 64Gb 3-bit/cell DDR NAND flash memory in 20nm-node technology

Recently, the demand for 3b/cell NAND flash has been increasing due to a strong market shift from 2b/cell to 3b/cell in NAND flash applications, such as USB disk drives, memory cards, MP3 players and digital still cameras that require cost-effective flash memory. To further expand the 3b/cell market, high write and read performances are essential [1]. Moreover, the device reliability requirements for these applications is a challenge due to continuing NAND scaling to sub-30nm pitches that increases cell-to-cell interference and disturbance. We present a high reliability 64Gb 3b/cell NAND flash with 7MB/s write rate and 200Mb/s asynchronous DDR interface in a 20m-node technology that helps to meet the expanding market demand and application requirement.
A 4GHz CT ΔΣ ADC with 70dB DR and −74dBFS THD in 125MHz BW

In this paper, a high-speed continuous-time (CT) ΔΣ ADC topology is proposed that absorbs the pole normally caused by the quantizer's input capacitance, while a local feedback loop compensates for the quantizer's excess delay. These measures allow a high-resolution multi-bit ΔΣ ADC to operate at GHz sampling rates. The bandwidth of this CMOS ΔΣ ADC is 6× wider than the state-of-the-art [1, 2]. Compared to a state-of-the-art pipeline BiCMOS ADC [3], it achieves similar power efficiency and bandwidth, but it only occupies 0.9mm<sup>2</sup> in 45nm CMOS, which is essential for low-cost integration. The 4b 3<sup>rd</sup>-order CT ΔΣ ADC is sampled at 4GHz and achieves 70dB DR and −74dBFS THD in a 125MHz BW while consuming 256mW. This prototype enables the use of ΔΣ ADCs in applications such as GSM base-stations and HD video systems.
Are there adverse consequences of quizzing during informed consent for HIV research?

Introduction While quizzing during informed consent for research to ensure understanding has become commonplace, it is unclear whether the quizzing itself is problematic for potential participants. In this study, we address this issue in a multinational HIV prevention research trial enrolling injection drug users in China and Thailand. Methods Enrolment procedures included an informed consent comprehension quiz. An informed consent survey followed. Results 525 participants completed the informed consent survey (Heng County, China=255, Xinjiang, China=229, Chiang Mai, Thailand=41). Mean age was 33 and mean educational level was 8 yrs. While quizzing was felt to be a good way to determine if a person understands the nature of clinical trial participation (97%) and participants did not generally find the quiz to be problematic, minorities of respondents felt pressured (6%); anxious (5%); bored (5%); minded (5%); and did not find the questions easy (13%). In multivariate analysis, lower educational level was associated with not minding the quizzing (6–10 yrs vs 0–5 yrs: OR=0.27, p=0.03; more than 11 yrs vs 0–5 yrs: OR=0.18, p=0.03). There were also site differences (Heng County vs Xinjiang) in feeling anxious (OR=0.07; p=<0.01), not minding (OR=0.26; p=0.03), being bored (OR=0.25; p=0.01) and not finding the questions easy (OR=0.10; p=<0.01). Conclusions Quizzing during the informed consent process can be problematic for a minority of participants. These problems may be associated with the setting in which research takes place and educational level. Further research is needed to develop, test and implement alternative methods of ensuring comprehension of informed consent. Trial Registration clinicaltrials.gov number NCT00270257.
The Changing Financial Landscape of Renal Transplant Practice: A National Cohort Analysis

Kidney transplantation has become more resource intensive as recipient complexity has increased and average donor quality has diminished over time. A national retrospective cohort study was performed to assess the impact of kidney donor and recipient characteristics on transplant center cost (exclusive of organ acquisition) and Medicare reimbursement. Data from the national transplant registry, University HealthSystem Consortium hospital costs, and Medicare payments for deceased donor (N = 53 862) and living donor (N = 36 715) transplants from 2002 to 2013 were linked and analyzed using multivariate linear regression modeling. Deceased donor kidney transplant costs were correlated with recipient (Expected Post Transplant Survival Score, degree of allosensitization, obesity, cause of renal failure), donor (age, cause of death, donation after cardiac death, terminal creatinine), and transplant (histocompatibility matching) characteristics. Living donor costs rose sharply with higher degrees of allosensitization, and were also associated with obesity, cause of renal failure, recipient work status, and 0‐ABDR mismatching. Analysis of Medicare payments for a subsample of 24 809 transplants demonstrated minimal correlation with patient and donor characteristics. In conclusion, the complexity in the landscape of kidney transplantation increases center costs, posing financial disincentives that may reduce organ utilization and limit access for higher‐risk populations.
A 4.6GHz 162Mb SRAM design in 22nm tri-gate CMOS technology with integrated active VMIN-enhancing assist circuitry

Future product applications demand increasing performance with reduced power consumption, which motivates the pursuit of high-performance at reduced operating voltages. Random and systematic device variations pose significant challenges to SRAM VMIN and low-voltage performance as technology scaling follows Moore's law to the 22nm node. A high-performance, voltage-scalable 162Mb SRAM array is developed in a 22nm tri-gate bulk technology featuring 3rd-generation high-k metal-gate transistors and 5th-generation strained silicon. Tri-gate technology reduces short-channel effects (SCE) and improves subthreshold slope to provide 37% improved device performance at 0.7V. Continuous device width sizing in planar technology is replaced by combining parallel silicon fins to multiply drive current. Process-circuit co-optimization of transient voltage collapse write assist (TVC-WA) and wordline underdrive read assist (WLUD-RA) features address process variation and fin quantization at 22nm and enable a 175mV reduction in the supply voltage required for 2GHz SRAM operation. Figure 13.1. 1 shows an SEM top-down view of a 0. 092μm2 high-density 6T SRAM bitcell (HDC) and a 0. 108μm2 low-voltage 6T SRAM cell (LVC) after gate and diffusion processing. Computational OPC/RET techniques extend the capabilities of 193nm immersion lithography to allow a 1.85× increase in array density relative to 32nm designs [1].
When Living Donor Liver Allografts Fail: Exploring the Outcomes of Retransplantation Using Deceased Donors

Outcomes of retransplantation after initial living donor liver transplantation (LDLT) are poorly understood. The aim of this study is to better understand the indications, timing, and outcomes of retransplantation after initial LDLT when compared to after initial deceased donor transplantation (DDLT). From 2002 to 2013, 209 retransplant recipients after initial LDLT and 2893 after initial DDLT were identified in Organ Procurement and Transplantation Network/United Network for Organ Sharing. Multivariable logistic models evaluated the association between initial transplant type and 1‐year mortality. The most frequent reason for early graft failure (≤14 days) in LDLT recipients was vascular thrombosis (63.6%) versus primary graft failure in initial DDLT recipients (59.1%). LDLT recipients were more often acutely and/or critically ill with a greater proportion of Status 1 (42.6% vs. 27.3%; p < 0.001) and intensive care unit (52.2% vs. 39.9%; p = 0.001) recipients at the time of retransplantation. There was no difference in adjusted 1‐year mortality between retransplant recipients after initial LDLT versus DDLT (odds ratio 0.74; 95% confidence interval 0.51–1.08). The proportion of recipients who ultimately required retransplantation for a third time was not different between the two groups (4.8%). Retransplantation outcomes after LDLT are not different from other retransplant procedures, despite recipients having greater acuity of illness and different indications.
Identification of the first recurrent PAR1 deletion in Léri-Weill dyschondrosteosis and idiopathic short stature reveals the presence of a novel SHOX enhancer

Background SHOX, located in the pseudoautosomal region 1 (PAR1) of the sexual chromosomes, encodes a transcription factor implicated in human growth. Defects in SHOX or its enhancers have been observed in ∼60% of Leri-Weill dyschondrosteosis (LWD) patients, a skeletal dysplasia characterised by short stature and/or the characteristic Madelung deformity, and in 2–5% of idiopathic short stature (ISS). To identify the molecular defect in the remaining genetically undiagnosed LWD and ISS patients, this study screened previously unanalysed PAR1 regions in 124 LWD and 576 ISS probands. Methods PAR1 screening was undertaken by multiplex ligation dependent probe amplification (MLPA). Copy number alterations were subsequently confirmed and delimited by locus-specific custom-designed MLPA, array comparative genomic hybridisation (CGH) and breakpoint junction PCR/sequencing. Results A recurrent PAR1 deletion downstream of SHOX spanning 47543 bp with identical breakpoints was identified in 19 LWD (15.3%) and 11 ISS (1.9%) probands, from 30 unrelated families. Eight evolutionarily conserved regions (ECRs 1–8) identified within the deleted sequence were evaluated for SHOX regulatory activity by means of chromosome conformation capture (3C) in chicken embryo limbs and luciferase reporter assays in human U2OS osteosarcoma cells. The 3C assay indicated potential SHOX regulatory activity by ECR1, which was subsequently confirmed to act as a SHOX enhancer, operating in an orientation and position independent manner, in human U2OS cells. Conclusions This study has identified the first recurrent PAR1 deletion in LWD and ISS, which results in the loss of a previously uncharacterised SHOX enhancer. The loss of this enhancer may decrease SHOX transcription, resulting in LWD or ISS due to SHOX haploinsufficiency.
The immunogenetics of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome

Immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome is a rare disorder in humans caused by germ-line mutations in the FOXP3 gene, a master transcriptional regulator for the development of CD4 regulatory T (Treg) cells. This T cell subset has global inhibitory functions that maintain immune homeostasis and mediate self-tolerance. Treg developmental deficiency or dysfunction is a hallmark of IPEX. It leads to severe, multi-organ, autoimmune phenomena including enteropathy, chronic dermatitis, endocrinopathy and other organ-specific diseases such as anaemia, thrombocytopenia, hepatitis and nephritis. In this review, the genetic, immunological and clinical characteristics of IPEX syndrome are described, and the impact of heritable mutations on the function of Treg cells highlighted.
Localized bacterial infection induces systemic activation of neutrophils through Cxcr2 signaling in zebrafish

Neutrophils are the first line of defense against tissue damage and are rapidly mobilized to sites of bacterial infection. However, the signals that regulate neutrophil recruitment are not well defined. Here, using photolabel‐enabled fate mapping in zebrafish larvae, we show that localized otic infection with Pseudomonas aeruginosa induces systemic activation and mobilization of neutrophils from the CHT through Cxcr2 signaling. We have cloned the zebrafish Cxcr1 and Cxcr2 receptors and show that Cxcr2 functions as a Cxcl8 receptor in live zebrafish. With the use of morpholino‐mediated depletion, we show that infection‐induced neutrophil mobilization from the CHT is mediated by Cxcr2 but not Cxcr1. By contrast, Cxcr2 depletion does not affect neutrophil recruitment to the chemoattractant LTB4. Taken together, our findings identify Cxcl8‐Cxcr2 signaling as an infection‐induced long‐range cue that mediates neutrophil motility and mobilization from hematopoietic tissues, positioning Cxcr2 as a critical pathway that mediates infection‐induced systemic activation of neutrophils.
ROS production in phagocytes: why, when, and where?

In the phagocytosis field, ROS production by the phagocyte NOX has been associated with pathogen killing for the last 50 years. Since the discovery of nonphagocyte NOX, numerous other roles for ROS production have been identified. Oxidative stress and ROS‐mediated signaling have received much attention in recent years. Much lower concentrations of ROS may be required for signaling compared with microbial killing. Based on the discoveries in nonphagocytic cells, it became logical to look for ROS functions distinct from pathogen killing, even in phagocytes. ROS are now linked to various forms of cell death, to chemotaxis, and to numerous modifications of cellular processes, including the NOX itself. ROS functions are clearly concentration‐dependent over a wide range of concentrations. How much is required for which function? Which species are required for how much time? Is ROS signaling only a side effect of bactericidal ROS production? One major obstacle to answer these questions is the difficulty of reliable quantitative ROS detection. Signal transduction often takes place on a subcellular scale over periods of seconds or minutes, so the detection methods need to provide appropriate time and space resolution. We present examples of local ROS production, decreased degradation, signaling events, and potentially ROS‐sensitive functions. We attempt to illustrate the current limitations for quantitative spatiotemporal ROS detection and point out directions for ongoing development. Probes for localized ROS detection and for combined detection of ROS, together with protein localization or other cellular parameters, are constantly improved.
32Gb/s 28nm CMOS time-interleaved transmitter compatible with NRZ receiver with DFE

We demonstrate that a 32Gb/s transmitter with a 4-way interleaved configuration is feasible in 28nm CMOS. A bit in the data stream contributes to a 2UI-wide pulse in the output signal, eliminating the need for 2-to-1 MUXs and enabling the use of quarter-rate clocking. A 4-tap 1UI-spacing FIR filter is implemented in the transmitter to compensate for the signal loss in the signal transmission media. The output signal is compatible with conventional NRZ receivers with a DFE.
Antimicrobial anxiety: the impact of stress on antimicrobial immunity

Leukocytes and epithelial cells are fundamental to antimicrobial immunity. Their antimicrobial responses are an evolutionarily conserved component of the innate immune system and are influenced by the host's response to external stimuli. The efficacy of host defense via antimicrobial responses derives from the ability of AMPs to rapidly identify and eradicate foreign microbes and activate proinflammatory pathways, and from the capacity of later innate and adaptive immune responses to amplify protection through distinct biochemical mechanisms. Recent advances in neuroimmunology have identified a direct link between the neuroendocrine and immune systems, where environmental stimuli are generally believed to promote a transient effect on the immune system in response to environmental challenges and are presumably brought back to baseline levels via neuroendocrine pathways. Stress is an environmental stimulus that flares from a variety of circumstances and has become engrained in human society. Small bouts of stress are believed to enhance the host's immune response; however, prolonged periods of stress can be detrimental through excess production of neuroendocrine‐derived mediators that dampen immune responses to invasive pathogens. Elucidation of the mechanisms behind stress‐induced immune modulation of antimicrobial responses will ultimately lead to the development of more effective therapeutic interventions for pathologic conditions. It is the intent of this review to broaden the existing paradigm of how stress‐related molecules dampen immune responses through suppression of antimicrobial mechanisms, and to emphasize that bacteria can use these factors to enhance microbial pathogenesis during stress.
A 28nm High-κ metal-gate single-chip communications processor with 1.5GHz dual-core application processor and LTE/HSPA+-capable baseband processor

The increase in the use and number of smartphone devices is causing heavy data traffic volumes on existing 3G mobile wireless networks. LTE, often referred to as 4G, offers true mobile broadband. It is a new network and access technology that provides new spectrum resources, much increased spectral efficiency, higher throughputs (150Mb/s with higher rates to come), at lower latency and it uses an IP-based infrastructure. LTE is the solution to mitigate the traffic load issue and it is being rolled out around the world. The proposed communication processor R-Mobile U2 (RMU2) achieves single-chip integration of a 1.5GHz dual-core application processor and a triple mode (GSM/WCDMA/LTE) base-band processor. Key design highlights of the RMU2 are: 1) A 28nm HKMG high-performance and low-leakage (HPL) CMOS bulk process achieves an optimal balance between both low leakage current and high performance. 2) A CPU clock control mechanism, called the “power saver”, limits the CPU power so as not to exceed a threshold level and to reduce IR drop. 3) The internal power domain is separated into 33 sub-blocks with I/O NMOS power switches [1] to minimize leakage current of any unused sub-block. 4) A dual-mode low-leakage SRAM [2] achieves low standby current in addition to conventional memory characteristics.
Early Conversion From Calcineurin Inhibitor‐ to Everolimus‐Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial

In a 24‐month, multicenter, open‐label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10–14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.732 versus −1.5(1.5) mL/min/1.732 (p = 0.116). Biopsy‐proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus‐treated patients (2.6%, p < 0.001) but similar to cyclosporine‐treated patients (8.8%, p = 0.755). Reporting on de novo donor‐specific antibodies (DSA) was limited but suggested more frequent anti‐HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10–14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.
Interaction of members of the heat shock protein‐70 family with the macrophage mannose receptor

The macrophage MR has been the subject of investigation for over 20 years, and several important physiological functions have been described. However, the molecular mechanisms that regulate MR signaling and trafficking during these processes still remain elusive. The focus of the current paper was to identify potential cellular MR‐interacting proteins. An initial screen of binding proteins in MR‐expressing cells was performed using coimmunoprecipitation, followed by identification of matching peptide sequences using proteomics and MS. The major class of binding proteins identified belonged to the heat shock family of proteins. The specific interaction of the MR with HSP70 family members was validated by Western blot analysis, ligand binding assays, and intracellular colocalization using confocal microscopy. Additional studies indicated that inhibition of the HSP BiP by treatment of cells with EGCG reduced BiP interaction with and surface expression of the MR. Studies of possible motifs within the cytoplasmic tail of the receptor suggested that a juxtamembrane dibasic sequence may contribute to the interaction with BiP. These findings suggest that the molecular association of the MR with HSP70 family members via the receptor cytoplasmic tail may contribute to MR trafficking in macrophages.
Surface Replacement of the Rheumatoid Elbow Through a Lateral Approach

Summary Total elbow replacement has become perhaps the most frequent surgical procedure for the rheumatoid elbow. It has become increasingly popular despite the lack of long-term follow-up reports for many implants, and it can be anticipated that more patients will demand the operation in the future. The stability of nonconstrained implants depends on the approach. In the lateral approach, the medial collateral ligament and the main part of the triceps tendon are preserved, which allows for proper soft tissue balancing. Wound complications are few and the lateral approach seems safe to use with the capitellocondylar type of prosthesis in rheumatoid elbows with reasonably well-preserved bone stock. The minimal amount of bone resection makes revision relatively easy regardless of whether you go for resection arthroplasty or exchange of the prosthesis.