Miracle-dz/UniFAR-FTUs huggingface dataset:
Separate endocytic pathways regulate IL‐5 receptor internalization and signaling

Eosinophils are critically dependent on IL‐5 for their activation, differentiation, survival, and augmentation of cytotoxic activity. We previously showed that the cytoplasmic domain of the hematopoietic receptor, βc, which is shared by IL‐5, IL‐3, and GM‐CSF, is directly ubiquitinated and degraded by the proteasomes in a JAK2‐dependent manner. However, studies describing the spatial distribution, endocytic regulation, and trafficking of βc‐sharing receptors in human eosinophils are currently lacking. Using deconvolution microscopy and biochemical methods, we clearly demonstrate that IL‐5Rs reside in and are internalized by clathrin‐ and lipid raft‐dependent endocytic pathways. Microscopy analyses in TF1 cells and human eosinophils revealed significant colocalization of βc, IL‐5Rα, and Cy3‐labeled IL‐5 with transferrin‐ (clathrin) and cholera toxin‐B‐ (lipid raft) positive vesicles. Moreover, whereas internalized IL‐5Rs were detected in both clathrin‐ and lipid raft‐positive vesicles, biochemical data revealed that tyrosine phosphorylated, ubiquitinated, and proteasome‐degraded IL‐5Rs partitioned to the soluble, nonraft fractions (clathrin‐containing). Lastly, we show that optimal IL‐5‐induced signaling requires entry of activated IL‐5Rs into the intracellular compartment, as coimmunoprecipitation of key signaling molecules with the IL‐5R was completely blocked when either endocytic pathway was inhibited. These data provide the first evidence that IL‐5Rs segregate and traffic into two distinct plasma membrane compartments, and they further establish that IL‐5R endocytosis regulates signaling both positively and negatively.
Frequencies of FoxP3+ naïve T cells are related to both viral load and naïve T cell proliferation responses in HIV disease

HIV infection results in depletion and dysfunction of naïve CD4+ T cells. The mechanisms underlying these deficiencies are not understood. We investigated the frequencies of CD4+ naïve subsets in HIV disease as defined by expression of CD25 and/or FoxP3 and the relationship of these frequencies to naïve T cell proliferation function. We observed increased proportions of CD25+FoxP3+ and CD25+FoxP3– cells and decreased proportions of CD25–FoxP3– cells within the naïve CD4+ cell compartment from HIV‐infected persons compared with findings in healthy donors. These perturbations were related to higher plasma HIV RNA levels but not with higher immune activation, as measured by the proportions of CD38+ memory CD4+ T cells. Naïve T cell proliferation responses to mitogen stimulation were inversely related to the frequencies and absolute numbers of FoxP3+ naïve T cells. MDA, a marker of oxidative stress, and sCD14, a marker of monocyte activation and a surrogate for microbial translocation, were increased in serum samples from HIV+ donors; however, neither marker was related to naïve T cell function in HIV+ donors. These observations suggest that alterations in naïve T cell subset frequencies could contribute to naïve T cell dysfunction in HIV disease, but these alterations are not necessarily the result of chronic immune activation.
Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease

Background Fabry disease (FD), a lysosomal storage disorder caused by α-galactosidase A (GLA) gene variants, has a heterogeneous phenotype. GLA variants can lead to classical FD, an attenuated non-classical phenotype, or no disease at all. This study investigates the value of plasma globotriaosylsphingosine (lysoGb3) to distinguish between these groups. This is of particular importance in the diagnosis of individuals with a GLA variant and an uncertain diagnosis of FD, lacking characteristic features of classical FD. Methods Subjects with GLA variants were grouped as classical, non-classical, uncertain or no FD, using strict phenotypical, biochemical and histological criteria. Plasma lysoGb3 was assessed by LC/MS/MS (normal ≤0.6 nmol/L). Results 154 subjects were grouped into classical (38 males (M), 66 females (F)), non-classical (13M, 14F), uncertain (5M, 9F) or no FD (6M, 3F). All subjects with a classical phenotype had elevated lysoGb3 values (M: range 45–150, F: 1.5–41.5). LysoGb3 values in patients with a non-classical phenotype (M: 1.3–35.7, F: 0.5–2.0) were different from healthy controls (M: p<0.01, F: p<0.05), but females overlapped with controls. In the no-FD group, lysoGb3 was normal. Conclusions LysoGb3 is a reliable diagnostic tool to discern classical FD from subjects without FD. This study suggests that the same applies to patients with a non-classical phenotype. LysoGb3 values of female patients overlap with controls. Consequently, in uncertain cases, increased lysoGb3 values are very suggestive for FD, but normal values cannot exclude FD. Confirmation in larger cohorts and data on the specificity of small lysoGb3 increases are necessary.
Neuroinvasive St. Louis Encephalitis Virus Infection in Solid Organ Transplant Recipients

In summer 2015, three unrelated solid organ transplant recipients in Phoenix, Arizona, had meningoencephalitis suggestive of West Nile virus (WNV) infection. Testing was inconclusive but was later confirmed as St. Louis encephalitis (SLE). We retrospectively reviewed clinical manifestations, treatment, and outcomes of these transplant recipients. Common symptoms were fever, rigors, diarrhea, headache, and confusion. One patient died 3 days after hospitalization. Therapy for the other two patients was initiated with interferon α‐2b (IFN) and intravenous IgG (IVIG; IFN plus IVIG in combination). Both patients tested positive for WNV by serologic assay, but SLE virus (SLEV) infection was later confirmed by plaque reduction neutralization test at a reference laboratory. Clinical improvement was observed within 72 h after initiation of IFN plus IVIG. SLEV has been an uncommon cause of neuroinvasive disease in the United States. Accurate, timely diagnosis is hindered because of clinical presentation similar to neuroinvasive WNV and SLE, serologic cross‐reactivity, and lack of a commercially available serologic assay for SLEV. There is currently no approved therapy for flaviviral neuroinvasive disease. Anecdotal reports indicate varying success with IFN, IVIG, or IFN plus IVIG in WNV neuroinvasive disease. The same regimen might be of value for immunocompromised persons with neuroinvasive SLEV infection.
IFN‐γ‐deficient mice develop IL‐1‐dependent cutaneous and musculoskeletal inflammation during experimental brucellosis

Human brucellosis exhibits diverse pathological manifestations that can affect almost any organ. In particular, osteoarticular complications are the most common focal manifestation of brucellosis and occur in 40–80% of patients. In immunocompetent mice, Brucella replication is generally restricted to the spleen, liver, and to a lesser extent, LNs, thereby limiting their use for study of focal inflammation often found in brucellosis. Here, we report that nasal, oral, or peritoneal infection of IFN‐γ−/− mice with WT Brucella melitensis or Brucella abortus results in joint and periarticular tissue inflammation. Histological analysis of the affected joints revealed inflammatory infiltrates and debris within the joint space colocalizing with Brucella antigen. Osteoarthritis, necrosis, periarticular soft tissue inflammation, and substantial brucellae burdens were observed. Oral rifampicin was effective in clearing infection and halting further progression of focal inflammation from infected IFN‐γ−/− mice, although some symptoms and swelling remained. Elevated IL‐1β, but not TNF‐α, IL‐6, or IL‐17, was detected in joint homogenates from infected IFN‐γ−/− mice. Whereas more susceptible to systemic infection, IL‐1R−/− mice depleted of IFN‐γ were more resistant to focal inflammation than WT mice similarly depleted of IFN‐γ. Collectively, these results show IFN‐γ−/− mice represent a potential model for study of focal inflammation attributed to Brucella infection and will allow evaluation of intervention strategies targeting IL‐1, IL‐1R, or other inflammatory mediators, with the potential to complement antibiotic‐based therapies.
4.1 14nm 6th-generation Core processor SoC with low power consumption and improved performance

Intel's 6th generation Core processor (code named “Skylake” or SKL) was designed to enable PC performance and user-experience at smaller and thinner form factors and enable fan-less PC platforms. It required optimization to an extremely low thermal design point (TDP). The lower average power consumption of SKL vs. the previous generation considerably increases the system battery life and allows full-day battery life or thinner designs with smaller batteries. The SKL product family is manufactured using an Intel 14nm tri-gate CMOS 11-metal-layer technology, as with the previous Core generation. Different dice include: 2 or 4 cores, a shared last-level cache (LLC, 1MB/core), a scalable graphic processor (GP) with 24, 48 or 72 execution units (EU), an image processing unit (IPU, supporting 4 cameras simultaneously), 2 channels of DDR3/LPDDR3/DDR4, a display engine (DE) and 3 display IO ports configurable to eDP, DP or HDMI. In mobile SKUs, the peripheral control hub (PCH) resides in the same package (MCP) as the CPU and communicates through an on-package IO (OPIO) bus. For desktop (DT), the PCH resides on the platform. Fig. 4.1. 1 presents the SKL block diagram for the minimum configuration (2 cores, 24 EU GP, MCP). A key challenge was the need to add new capabilities, while reducing power, especially for some of the popular uses (media, casual gaming, speech recognition and advanced imaging).
6.8 A 1.5V 33Mpixel 3D-stacked CMOS image sensor with negative substrate bias

3D stacking and computational imaging are two major driving forces for CMOS image sensors. In addition, 3D stacking separates pixel array and peripheral circuits. As such, computational imaging blocks (stereo vision, array camera, reconfigurable instruction cell array, etc.) can integrate with sensor circuits while leveraging advanced CMOS technologies including FinFET. To accommodate this trend, we need to design blocks such as comparators, readouts, transmitters, and PLLs, using digital architectures in logic processes with a minimum number of resistors and capacitors. Achieving 100% array-to-chip area ratio is an ultimate goal of 3D CIS. For this reason, all peripheral circuits must be under the pixel array. However, row and column circuits may overlap at the corner if both pitches are equal to pixel pitch. To avoid this issue, we make row and pixel pitch the same, and shrink column pitch to 82% to spread the column signal to array width using the “river routing” tools introduced for display-driver ICs, as shown in Fig. 6.8. 1. The 3D stacking technology we apply [1] is top-metal face-to-face, and it can put 3D connections under a backside-illuminated pixel array. Therefore it increases array-to-chip area ratio comparing with a TSV chip that uses area outside the pixel array. This chip demonstrates the 3D connections at the center of the uniform 33Mpixel array and seamless image readout using 4 identical 8.3Mpixel circuit units. Instead of developing new circuitry, we can combine 16 compact units for 133Mpixel at the same frame rate and save the extra driving power.
Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO

Background The non-POU domain containing octamer-binding gene (NONO) is located on chromosome Xq13.1 and encodes a member of a small family of RNA-binding and DNA-binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Loss-of-function variants in NONO have been described as a cause of intellectual disability in males but have not been described in association with congenital heart defects or cardiomyopathy. In this article, we seek to further define the phenotypic consequences of NONO depletion in human subjects. Methods We searched a clinical database of over 6000 individuals referred for exome sequencing and over 60 000 individuals referred for CNV analysis. Results We identified two males with atrial and ventricular septal defects, left ventricular non-compaction (LVNC), developmental delay and intellectual disability, who harboured de novo, loss-of-function variants in NONO. We also identified a male infant with developmental delay, congenital brain anomalies and severe LVNC requiring cardiac transplantation, who inherited a single-gene deletion of NONO from his asymptomatic mother. Conclusions We conclude that in addition to global developmental delay and intellectual disability, males with loss-of-function variants in NONO may also be predisposed to developing congenital heart defects and LVNC with the penetrance of these cardiac-related problems being influenced by genetic, epigenetic, environmental or stochastic factors. Brain imaging of males with NONO deficiency may reveal structural defects with abnormalities of the corpus callosum being the most common. Although dysmorphic features vary between affected individuals, relative macrocephaly is a common feature.
Survival and causes of death in patients with von Hippel-Lindau disease

Background Historically, the survival of patients with von Hippel-Lindau disease (vHL) has been poorer than that of the general population. We aimed to determine whether the survival of VHL mutation carriers and their risk of vHL-related death has changed over time and how it has been affected by sex, genotype and surveillance attendance. Methods In a retrospective cohort study, we included all known Danish vHL families with a VHL mutation. We assessed the survival and causes of death for 143 VHL mutation carriers using Cox regression models and compared vHL survival with that of 137 siblings without vHL. vHL life expectancy was compared with the general population using a relative survival model. Results The estimated mean life expectancies for male and female patients born in 2000 were 67 and 60 years, respectively. Survival is influenced by the sex and genotype of the patient. Female patients have a significantly higher risk of vHL-related death than male patients (HR=2.25, 95% CI 1.20 to 4.20, p=0.011). Overall, 79% (53 of 67) of deaths were vHL-related, but the risk of vHL-related death has decreased over time, as has the frequency of renal cell carcinoma (RCC)-related death. Surveillance is especially beneficial for truncating mutation carriers, who have the greatest RCC and central nervous system (CNS) hemangioblastoma risk. Conclusions vHL survival has improved over time and has become closer to that of siblings without vHL and the general population. Even though the risk of vHL-related death has decreased significantly, the main cause of death is still CNS hemangioblastomas and hence improved treatment options are essential.
Differential T cell homing to colon vs. small intestine is imprinted by local CD11c+ APCs that determine homing receptors

Mechanisms that imprint T cell homing to the small intestine have been well studied; however, those for homing to the colon are poorly understood. Recently, we found that these are distinct subcompartments of the gut mucosal immune system, which implies differential homing. Here, we show that colonic CD11c+ APCs imprint CD8+ T cell preferential homing to the colon, in contrast to those from the small intestine that imprint CD8+ T cell homing to the small intestine, and that the differences are related to the variable ability of APCs to induce α4β7‐integrin and CCR9 expression on T cells. Colon APCs also expressed lower levels of retinoic acid–producing enzymes that are known to control the mucosal homing of T cells. These findings are the first to our knowledge to directly demonstrate that colon APCs imprint T cells to selectively home to the large bowel, which is critical for the design of successful T cell–based therapies and vaccines, such as colon cancer immunotherapy and HIV vaccines.
Facing Time Limits and Kinship Placements

The study examines the relationship between temporary welfare time limits and foster care relative placement in Nevada. A logit model was specified with a binary dependent variable capturing placement with relatives as opposed to nonrelative family foster care placement or group care. The findings reveal that, all else constant, children from welfare families with more months counted toward their Nevada's time limits are not more likely to be placed with relatives than their counterparts. The findings also show that children from African American families, from large families, or from families receiving cash during removal are more likely to be placed with relatives. The authors suggest that casework activities need to occur before, during, and after children experience foster care placements with relatives.
Thymic function is a major determinant of onset of antibody‐mediated rejection in heart transplantation

Thymic function decreases progressively with age but may be boosted in certain circumstances. We questioned whether heart transplantation was such a situation and whether thymic function was related to the onset of rejection. Twenty‐eight antithymocyte globulin–treated heart transplant recipients were included. Patients diagnosed for an antibody‐mediated rejection on endomyocardial biopsy had a higher proportion of circulating recent thymic emigrant CD4+ T cells and T cell receptor excision circle levels than other transplanted subjects. Thymus volume and density, assessed by computed tomography in a subset of patients, was also higher in patients experiencing antibody‐mediated rejection. We demonstrate that thymic function is a major determinant of onset of antibody‐mediated rejection and question whether thymectomy could be a prophylactic strategy to prevent alloimmune humoral responses.
Geographic disparity in kidney transplantation under KAS

The Kidney Allocation System fundamentally altered kidney allocation, causing a substantial increase in regional and national sharing that we hypothesized might impact geographic disparities. We measured geographic disparity in deceased donor kidney transplant (DDKT) rate under KAS (6/1/2015‐12/1/2016), and compared that with pre‐KAS (6/1/2013‐12/3/2014). We modeled DSA‐level DDKT rates with multilevel Poisson regression, adjusting for allocation factors under KAS. Using the model we calculated a novel, improved metric of geographic disparity: the median incidence rate ratio (MIRR) of transplant rate, a measure of DSA‐level variation that accounts for patient casemix and is robust to outlier values. Under KAS, MIRR was 1.751.811.86 for adults, meaning that similar candidates across different DSAs have a median 1.81‐fold difference in DDKT rate. The impact of geography was greater than the impact of factors emphasized by KAS: having an EPTS score ≤20% was associated with a 1.40‐fold increase (IRR = 1.351.401.45, P < .01) and a three‐year dialysis vintage was associated with a 1.57‐fold increase (IRR = 1.561.571.59, P < .001) in transplant rate. For pediatric candidates, MIRR was even more pronounced, at 1.661. 922.27. There was no change in geographic disparities with KAS (P = .3). Despite extensive changes to kidney allocation under KAS, geography remains a primary determinant of access to DDKT.
14.2 DNPU: An 8.1TOPS/W reconfigurable CNN-RNN processor for general-purpose deep neural networks

Recently, deep learning with convolutional neural networks (CNNs) and recurrent neural networks (RNNs) has become universal in all-around applications. CNNs are used to support vision recognition and processing, and RNNs are able to recognize time varying entities and to support generative models. Also, combining both CNNs and RNNs can recognize time varying visual entities, such as action and gesture, and to support image captioning [1]. However, the computational requirements in CNNs are quite different from those of RNNs. Fig. 14.2. 1 shows a computation and weight-size analysis of convolution layers (CLs), fully-connected layers (FCLs) and RNN-LSTM layers (RLs). While CLs require a massive amount of computation with a relatively small number of filter weights, FCLs and RLs require a relatively small amount of computation with a huge number of filter weights. Therefore, when FCLs and RLs are accelerated with SoCs specialized for CLs, they suffer from high memory transaction costs, low PE utilization, and a mismatch of the computational patterns. Conversely, when CLs are accelerated with FCL- and RL-dedicated SoCs, they cannot exploit reusability and achieve required throughput. So far, works have considered acceleration of CLs, such as [2–4], or FCLs and RLs like [5]. However, there has been no work on a combined CNN-RNN processor. In addition, a highly reconfigurable CNN-RNN processor with high energy-efficiency is desirable to support general-purpose deep neural networks (DNNs).
The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell–mediated rejection, antibody‐mediated rejection, and prospects for integrative endpoints for next‐generation clinical trials

The kidney sessions of the 2017 Banff Conference focused on 2 areas: clinical implications of inflammation in areas of interstitial fibrosis and tubular atrophy (i‐IFTA) and its relationship to T cell–mediated rejection (TCMR), and the continued evolution of molecular diagnostics, particularly in the diagnosis of antibody‐mediated rejection (ABMR). In confirmation of previous studies, it was independently demonstrated by 2 groups that i‐IFTA is associated with reduced graft survival. Furthermore, these groups presented that i‐IFTA, particularly when involving >25% of sclerotic cortex in association with tubulitis, is often a sequela of acute TCMR in association with underimmunosuppression. The classification was thus revised to include moderate i‐IFTA plus moderate or severe tubulitis as diagnostic of chronic active TCMR. Other studies demonstrated that certain molecular classifiers improve diagnosis of ABMR beyond what is possible with histology, C4d, and detection of donor‐specific antibodies (DSAs) and that both C4d and validated molecular assays can serve as potential alternatives and/or complements to DSAs in the diagnosis of ABMR. The Banff ABMR criteria are thus updated to include these alternatives. Finally, the present report paves the way for the Banff scheme to be part of an integrative approach for defining surrogate endpoints in next‐generation clinical trials.
New development in studies of formyl‐peptide receptors: critical roles in host defense

Formyl‐peptide receptors are a family of 7 transmembrane domain, Gi‐protein‐coupled receptors that possess multiple functions in many pathophysiologic processes because of their expression in a variety of cell types and their capacity to interact with a variety of structurally diverse, chemotactic ligands. Accumulating evidence demonstrates that formyl‐peptide receptors are critical mediators of myeloid cell trafficking in the sequential chemotaxis signal relays in microbial infection, inflammation, and immune responses. Formyl‐peptide receptors are also involved in the development and progression of cancer. In addition, one of the formyl‐peptide receptor family members, Fpr2, is expressed by normal mouse‐colon epithelial cells, mediates cell responses to microbial chemotactic agonists, participates in mucosal development and repair, and protects against inflammation‐associated tumorigenesis. These novel discoveries greatly expanded the current understanding of the role of formyl‐peptide receptors in host defense and as potential molecular targets for the development of therapeutics.