Miracle-dz/UniFAR-FTUs huggingface dataset:
c‐Maf activates the promoter and enhancer of the IL‐21 gene, and TGF‐β inhibits c‐Maf‐induced IL‐21 production in CD4+ T cells

Previous studies have shown that IL‐6 potently induces IL‐21 production in CD4+ T cells, whereas TGF‐β inhibits IL‐6‐induced IL‐21 production in CD4+ T cells. In this study, we addressed the mechanisms underlying the transcriptional regulation of IL‐21 production in CD4+ T cells. We found that IL‐6 induced c‐Maf expression in CD4+ T cells and that the enforced expression of c‐Maf induced IL‐21 production in CD4+ T cells without IL‐6, IL‐4/STAT6 signaling, or an autocrine effect of IL‐21. Moreover, we found that c‐Maf directly bound to and activated IL‐21P and the CNS‐2 enhancer through MARE sites. On the other hand, we also found that although TGF‐β up‐regulated IL‐6‐induced c‐Maf expression in CD4+ T cells, TGF‐β inhibited c‐Maf‐induced IL‐21 production in CD4+ T cells. Finally, we found that Foxp3 bound to IL‐21P and the CNS‐2 enhancer and inhibited c‐Maf‐induced IL‐21 production modestly but significantly in CD4+ T cells. Taken together, these results suggest that c‐Maf induces IL‐21 production directly in CD4+ T cells by activating IL‐21P and the CNS‐2 enhancer and that TGF‐β suppresses c‐Maf‐induced IL‐21 production in CD4+ T cells.
A 32nm Westmere-EX Xeon® enterprise processor

The next-generation enterprise Xeon® processor [1] consists of 10 Westmere 32nm cores [2] and a shared inclusive L3 cache (LLC) integrated on a monolithic die, with link-based I/Os. This paper focuses on the innovations and circuit optimizations over the predecessor [3] targeting idle power reduction, robust high-speed I/O links, and performance per watt improvements. The processor is implemented in 32nm CMOS using high-κ metal gate transistors and nine copper interconnect layers [4].
Adenosine modifies the balance between membrane and soluble forms of Flt‐1

VEGFR‐1 (or Flt‐1) exists under a sFlt‐1 or a mFlt‐1 form. sFlt‐1 is antiangiogenic, and mFlt‐1 is proangiogenic. The cardioprotective nucleoside Ado is proangiogenic, but its effects on Flt‐1 are unknown and were tested in this study. In primary human macrophages from healthy volunteers, Ado inhibited sFlt‐1 expression induced by LPS (–43%, P=0.006), HS, and IL‐1β but not hypoxia. This effect was also observed in macrophages from patients with acute MI (–33%, P<0.001). It was reproduced by the A2A Ado receptor agonist CGS21680 and abrogated by the A2A antagonist SCH58261. Conversely, Ado increased mFlt‐1 expression, thus switching sFlt‐1 from the soluble toward the membrane form. This switch was also present in macrophages from acute MI patients (P<0.001). Assessment of HIF‐1α nuclear translocation and activation together with siRNA experiments suggested that the effect of Ado on Flt‐1 involves HIF‐1α. In conclusion, Ado down‐regulates sFlt‐1 and up‐regulates mFlt‐1 production, an effect that indicates that Ado may be used to stimulate angiogenesis in the heart.
Pregnancy Outcomes Related to Mycophenolate Exposure in Female Kidney Transplant Recipients

In 2012, the U.S. Food and Drug Administration issued guidelines advising kidney transplant recipients (KTRs) to discontinue mycophenolate (MPA) in preparation for pregnancy. Little is known about how this guidance has affected pregnancy and graft outcomes. The purpose of this retrospective cohort study was to investigate any association between the discontinuation of MPA and KTR pregnancy and graft outcomes. Data from the National Transplantation Pregnancy Registry included 382 cases in which KTRs managed on MPA became pregnant. Overall, 22 variables, including the time in which a KTR discontinued MPA, were assessed across four end points: miscarriages, birth defects, and 2‐ and 5‐year postpartum graft loss. Birth defects and miscarriages were similar among KTRs who discontinued MPA >6 and <6 weeks prior to pregnancy and during the first trimester. In contrast, discontinuing MPA during the second trimester or later significantly increased the risk of miscarriages (odds ratio [OR] 9.35, 95% confidence interval [CI] 4.31–20.00, p < 0.001) and birth defects (OR 6.06, 95% CI 1.96–18.87, p = 0.002). Discontinuing MPA <6 weeks prior to pregnancy was associated with an increased risk of 5‐year graft loss. For the fetus, there is value to discontinuing MPA anytime prior to the second trimester. Adhering to current guidelines does not negatively affect graft survival.
Infant homicide and accidental death in the United States, 1940–2005: ethics and epidemiological classification

Potential ethical issues can arise during the process of epidemiological classification. For example, unnatural infant deaths are classified as accidental deaths or homicides. Societal sensitivity to the physical abuse and neglect of children has increased over recent decades. This enhanced sensitivity could impact reported infant homicide rates. Infant homicide and accident mortality rates in boys and girls in the USA from 1940 to 2005 were analysed. In 1940, infant accident mortality rates were over 20 times greater than infant homicide rates in both boys and girls. After about 1980, when the ratio of infant accident mortality rates to infant homicide rates decreased to less than five, and the sum of infant accident and homicide rates became relatively constant, further decreases in infant accident mortality rates were associated with increases in reported infant homicide rates. These findings suggest that the dramatic decline of accidental infant mortality and recent increased societal sensitivity to child abuse may be related to the increased infant homicide rates observed in the USA since 1980 rather than an actual increase in societal violence directed against infants. Ethical consequences of epidemiological classification, involving the principles of beneficence, non-maleficence and justice, are suggested by observed patterns in infant accidental deaths and homicides in the USA from 1940 to 2005.
Biogenic amines activate blood leukocytes via trace amine‐associated receptors TAAR1 and TAAR2

Certain biogenic amines, such as 2‐PEA, TYR, or T1AM, modulate blood pressure, cardiac function, brain monoaminergic systems, and olfaction‐guided behavior by specifically interacting with members of a group of rhodopsin‐like receptors, TAAR. A receptor that is absent from olfactory epithelia but had long been identified in the brain and a variety of peripheral tissues, TAAR1 has been found recently in blood B cells, suggesting a functional role of TAAR1 in these cells. With the present study, we have set out to clarify the expression and functional roles of TAAR in different isolated human blood leukocyte types. Here, we report the functional expression of TAAR1 and its closest relative TAAR2 in blood PMN and T and B cells. Both receptors are coexpressed in a subpopulation of PMN, where they are necessary for the chemosensory migration toward the TAAR1 ligands 2‐PEA, TYR, and T1AM, with EC50 values of 0.43 ± 0.05 nM, 0.52 ± 0.05 nM, and 0.25 ± 0.04 nM, respectively. The same amines, with similar potencies, triggered cytokine or Ig secretion, in purified blood T or B cells, respectively. Notably, 2‐PEA regulated mRNA expression of 28 T cell function‐related genes, above all of the CCL5. In siRNA‐guided experiments, TAAR1 and TAAR2 proved to be necessary for amine‐induced blood leukocyte functions. In summary, our results demonstrate that biogenic amines potently regulate blood cell functions via TAAR1 and TAAR2 and open the perspective of their specific pharmacological modulation.
Impact of Mixed Xenogeneic Porcine Hematopoietic Chimerism on Human NK Cell Recognition in a Humanized Mouse Model

Mixed chimerism is a promising approach to inducing allograft and xenograft tolerance. Mixed allogeneic and xenogeneic chimerism in mouse models induced specific tolerance and global hyporesponsiveness, respectively, of host mouse natural killer (NK) cells. In this study, we investigated whether pig/human mixed chimerism could tolerize human NK cells in a humanized mouse model. Our results showed no impact of induced human NK cell reconstitution on porcine chimerism. NK cells from most pig/human mixed chimeric mice showed either specifically decreased cytotoxicity to pig cells or global hyporesponsiveness in an in vitro cytotoxicity assay. Mixed xenogeneic chimerism did not hamper the maturation of human NK cells but was associated with an alteration in NK cell subset distribution and interferon gamma (IFN‐γ) production in the bone marrow. In summary, we demonstrate that mixed xenogeneic chimerism induces human NK cell hyporesponsiveness to pig cells. Our results support the use of this approach to inducing xenogeneic tolerance in the clinical setting. However, additional approaches are required to improve the efficacy of tolerance induction while ensuring adequate NK cell functions.
A 58nm 1.8V 1Gb PRAM with 6.4MB/s program BW

In mobile systems, the demand for the energy saving continues to require a low power memory sub-system. During the last decade, the floating-gate flash memory has been an indispensable low power memory solution. However, NOR flash memory has begun to show difficulties in scaling due to the device's reliability and yield issues. Over the past few years, phase-change random access memory (PRAM) has emerged as an alternative non-volatile memory (NVM) owing to its promising scalability and low cost process [1,2]. In this paper, a PRAM, implemented in a 58nm PRAM process with a low power double-data-rate nonvolatile memory (LPDDR2-N) interface, is presented [3].
The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques

Although stable mixed‐hematopoietic chimerism induces robust immune tolerance to solid organ allografts in mice, the translation of this strategy to large animal models and to patients has been challenging. We have previously shown that in MHC‐matched nonhuman primates (NHPs), a busulfan plus combined belatacept and anti‐CD154‐based regimen could induce long‐lived myeloid chimerism, but without T cell chimerism. In that setting, donor chimerism was eventually rejected, and tolerance to skin allografts was not achieved. Here, we describe an adaptation of this strategy, with the addition of low‐dose total body irradiation to our conditioning regimen. This strategy has successfully induced multilineage hematopoietic chimerism in MHC‐matched transplants that was stable for as long as 24 months posttransplant, the entire length of analysis. High‐level T cell chimerism was achieved and associated with significant donor‐specific prolongation of skin graft acceptance. However, we also observed significant infectious toxicities, prominently including cytomegalovirus (CMV) reactivation and end‐organ disease in the setting of functional defects in anti‐CMV T cell immunity. These results underscore the significant benefits that multilineage chimerism‐induction approaches may represent to transplant patients as well as the inherent risks, and they emphasize the precision with which a clinically successful regimen will need to be formulated and then validated in NHP models.
wANNOVAR: annotating genetic variants for personal genomes via the web

Background High-throughput DNA sequencing platforms have become widely available. As a result, personal genomes are increasingly being sequenced in research and clinical settings. However, the resulting massive amounts of variants data pose significant challenges to the average biologists and clinicians without bioinformatics skills. Methods and results We developed a web server called wANNOVAR to address the critical needs for functional annotation of genetic variants from personal genomes. The server provides simple and intuitive interface to help users determine the functional significance of variants. These include annotating single nucleotide variants and insertions/deletions for their effects on genes, reporting their conservation levels (such as PhyloP and GERP++ scores), calculating their predicted functional importance scores (such as SIFT and PolyPhen scores), retrieving allele frequencies in public databases (such as the 1000 Genomes Project and NHLBI-ESP 5400 exomes), and implementing a ‘variants reduction’ protocol to identify a subset of potentially deleterious variants/genes. We illustrated how wANNOVAR can help draw biological insights from sequencing data, by analysing genetic variants generated on two Mendelian diseases. Conclusions We conclude that wANNOVAR will help biologists and clinicians take advantage of the personal genome information to expedite scientific discoveries. The wANNOVAR server is available at http://wannovar.usc. edu, and will be continuously updated to reflect the latest annotation information.
Effect of Replacing Race With Apolipoprotein L1 Genotype in Calculation of Kidney Donor Risk Index

Renal allografts from deceased African American donors with two apolipoprotein L1 gene (APOL1) renal‐risk variants fail sooner than kidneys from donors with fewer variants. The Kidney Donor Risk Index (KDRI) was developed to evaluate organ offers by predicting allograft longevity and includes African American race as a risk factor. Substituting APOL1 genotype for race may refine the KDRI. For 622 deceased African American kidney donors, we applied a 10‐fold cross‐validation approach to estimate contribution of APOL1 variants to a revised KDRI. Cross‐validation was repeated 10 000 times to generate distribution of effect size associated with APOL1 genotype. Average effect size was used to derive the revised KDRI weighting. Mean current‐KDRI score for all donors was 1.4930 versus mean revised‐KDRI score 1.2518 for 529 donors with no or one variant and 1.8527 for 93 donors with two variants. Original and revised KDRIs had comparable survival prediction errors after transplantation, but the spread in Kidney Donor Profile Index based on presence or absence of two APOL1 variants was 37 percentage points. Replacing donor race with APOL1 genotype in KDRI better defines risk associated with kidneys transplanted from deceased African American donors, substantially improves KDRI score for 85–90% of kidneys offered, and enhances the link between donor quality and recipient need.
X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face

Background We present a large Dutch family with seven males affected by a novel syndrome of X-linked intellectual disability, hypogonadism, gynaecomastia, truncal obesity, short stature and recognisable craniofacial manifestations resembling but not identical to Wilson-Turner syndrome. Seven female relatives show a much milder expression of the phenotype. Methods and results We performed X chromosome exome (X-exome) sequencing in five individuals from this family and identified a novel intronic variant in the histone deacetylase 8 gene (HDAC8), c.164+5G>A, which disturbs the normal splicing of exon 2 resulting in exon skipping, and introduces a premature stop at the beginning of the histone deacetylase catalytic domain. The identified variant completely segregates in this family and was absent in 96 Dutch controls and available databases. Affected female carriers showed a notably skewed X-inactivation pattern in lymphocytes in which the mutated X-chromosome was completely inactivated. Conclusions HDAC8 is a member of the protein family of histone deacetylases that play a major role in epigenetic gene silencing during development. HDAC8 specifically controls the patterning of the skull with the mouse HDAC8 knock-out showing craniofacial deformities of the skull. The present family provides the first evidence for involvement of HDAC8 in a syndromic form of intellectual disability.
A Novel Xenogeneic Graft‐Versus‐Host Disease Model for Investigating the Pathological Role of Human CD4+ or CD8+ T Cells Using Immunodeficient NOG Mice

Graft‐versus‐host disease (GVHD) is a major complication of allogenic bone marrow transplantation and involves the infiltration of donor CD4+ and/or CD8+ T cells into various organs of the recipient. The pathological role of human CD4+ and CD8+ T cells in GVHD remains controversial. In this study, we established two novel xenogeneic (xeno)‐GVHD models. Human CD4+ or CD8+ T cells were purified from peripheral blood and were transplanted into immunodeficient NOD/Shi‐scid IL2rgnull (NOG) mice. Human CD8+ T cells did not induce major GVHD symptoms in conventional NOG mice. However, CD8+ T cells immediately proliferated and induced severe GVHD when transferred into NOG mice together with at least 0.5 × 106 CD4+ T cells or into NOG human interleukin (IL)‐2 transgenic mice. Human CD4+ T cell–transplanted NOG mice developed skin inflammations including alopecia, epidermal hyperplasia, and neutrophilia. Pathogenic T helper (Th)17 cells accumulated in the skin of CD4+ T cell–transplanted NOG mice. Further, an anti‐human IL‐17 antibody (secukinumab) significantly suppressed these skin pathologies. These results indicate that pathogenic human Th17 cells induce cutaneous GVHD via IL‐17–dependent pathways. This study provides fundamental insights into the pathogenesis of xeno‐GVHD, and these humanized mouse models may be useful as preclinical tools for the prevention of GVHD.
Variation in Access to Kidney Transplantation Across Renal Programs in Ontario, Canada

In the United States, kidney transplant rates vary significantly across end‐stage renal disease (ESRD) networks. We conducted a population‐based cohort study to determine whether there was variability in kidney transplant rates across renal programs in a health care system distinct from the United States. We included incident chronic dialysis patients in Ontario, Canada, from 2003 to 2013 and determined the 1‐, 5‐, and 10‐year cumulative incidence of kidney transplantation in 27 regional renal programs (similar to U.S. ESRD networks). We also assessed the cumulative incidence of kidney transplant for “healthy” dialysis patients (aged 18–50 years without diabetes, coronary disease, or malignancy). We calculated standardized transplant ratios (STRs) using a Cox proportional hazards model, adjusting for patient characteristics (maximum possible follow‐up of 11 years). Among 23 022 chronic dialysis patients, the 10‐year cumulative incidence of kidney transplantation ranged from 7.4% (95% confidence interval [CI] 4.8–10.7%) to 31.4% (95% CI 16.5–47.5%) across renal programs. Similar variability was observed in our healthy cohort. STRs ranged from 0.3 (95% CI 0.2–0.5) to 1.5 (95% CI 1.4–1.7) across renal programs. There was significant variation in kidney transplant rates across Ontario renal programs despite patients having access to the same publicly funded health care system.
A TEST FOR RETINAL FUNCTION IN CATARACTOUS PATIENTS

It is often the source of much chagrin to both patient and operator when, following the removal of a cataract from an eye which had apparently projected light perfectly, a great defect is discovered in the macular region. The patient has had his hope of useful vision abruptly shattered, and the operator feels cheated out of the rewards of a trying and hazardous venture. Unfortunately, a history of previous visual acuity from the patient is not always reliable, and the projection test as ordinarily practiced does not reveal central retinal changes. The means of producing a very feeble illumination for testing macular perception are not always available. While experimenting with entoptic phenomena, it occurred to me that the subjective visualization of one's own retina might be employed in detecting central lesions or central amblyopia. The method is well known. One removes the head from the electric ophthalmoscope and places
Oculo-auriculo-vertebral spectrum: a review of the literature and genetic update

Oculo-auriculo-vertebral spectrum (OAVS, OMIM 164 210) is a developmental disorder primarily involving structures derived from the first and second pharyngeal arches during embryogenesis. The phenotype is clinically heterogeneous and is typically characterised by abnormal development of the ear, mandible anomalies and defects of the vertebral column. OAVS may occur as a multiple congenital abnormality, and associated findings include anomalies of the eye, brain, heart, kidneys and other organs and systems. Both genetic and environmental factors are thought to contribute to this craniofacial condition, however, the mechanisms are still poorly understood. Here, we present a review of the literature on OAVS, discussing what is known about the aetiology, candidate loci, possible mechanisms and the range of clinical features that characterise this condition. We also comment on some important aspects of recurrence risk counselling to aid clinical management.
THE IMPACT OF LEFT VENTRICULAR DIASTOLIC DYSFUNCTION ON LUNG TRANSPLANT OUTCOME IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION

Diastolic dysfunction may influence perioperative outcome, early graft function and long-term survival. We compared the outcomes of DLTx for PAH patients with pre-operative LV diastolic dysfunction to those without diastolic dysfunction. Of 116 consecutive patients with PAH (who underwent transplantation between January 1995 and December 2013), 44 met our inclusion and exclusion criteria. Fourteen patients (31.8%) with diastolic dysfunction pre-LTx had a higher BMI [29 (IQR 21.5-32.6) vs. 22.4 (IRQ 19.9-25.3)], mean pulmonary arterial pressure (54.6 ± 10 mmHg vs. 47 ± 11.3 mmHg) and right atrial pressure (16.5 ± 5.2 mmHg vs. 10.6 ± 5.2 mmHg). They received extracorporeal life support more frequently [33% vs 7% (p=0.02)], had worse Apache II score, 21.7 ± 7.4 vs 15.3 ± 5.3 (p=0.02), and a trend toward worse ventilator-free days 2.5 (IQR 6.5 – A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. 32.5) vs. 17 (IQR 3 – 23) (p=0.08). There was no effect on development of primary graft dysfunction or ICU / hospital survival. One-year survival was worse (HR 4.45, 95% CI 1.3-22, p=0.02). Diastolic dysfunction was the only variable that correlated with overall survival (HR 5.4, 95% CI 1.3-22, P=0.02). Diastolic dysfunction leads to early post-operative morbidity and worse survival in PAH patients after double lung transplant.
Mutation in cytochrome b gene of mitochondrial DNA in a family with fibromyalgia is associated with NLRP3-inflammasome activation

Background Fibromyalgia (FM) is a worldwide diffuse musculoskeletal chronic pain condition that affects up to 5% of the general population. Many symptoms associated with mitochondrial diseases are reported in patients with FM such as exercise intolerance, fatigue, myopathy and mitochondrial dysfunction. In this study, we report a mutation in cytochrome b gene of mitochondrial DNA (mtDNA) in a family with FM with inflammasome complex activation. Methods mtDNA from blood cells of five patients with FM were sequenced. We clinically and genetically characterised a patient with FM and family with a new mutation in mtCYB. Mitochondrial mutation phenotypes were determined in skin fibroblasts and transmitochondrial cybrids. Results After mtDNA sequence in patients with FM, we found a mitochondrial homoplasmic mutation m.15804T>C in the mtCYB gene in a patient and family, which was maternally transmitted. Mutation was observed in several tissues and skin fibroblasts showed a very significant mitochondrial dysfunction and oxidative stress. Increased NLRP3-inflammasome complex activation was observed in blood cells from patient and family. Conclusions We propose further studies on mtDNA sequence analysis in patients with FM with evidences for maternal inheritance. The presence of similar symptoms in mitochondrial myopathies could unmask mitochondrial diseases among patients with FM. On the other hand, the inflammasome complex activation by mitochondrial dysfunction could be implicated in the pathophysiology of mitochondrial diseases.