For the development of new 5G systems to operate in bands up to 100 GHz, there is a need for accurate radio propagation models at these bands that currently are not addressed by existing channel models developed for bands below 6 GHz. This document presents a preliminary overview of 5G channel models for bands up to 100 GHz. These have been derived based on extensive measurement and ray tracing results across a multitude of frequencies from 6 GHz to 100 GHz, and this document describes an initial 3D channel model which includes: 1) typical deployment scenarios for urban microcells (UMi) and urban macrocells (UMa), and 2) a baseline model for incorporating path loss, shadow fading, line of sight probability, penetration and blockage models for the typical scenarios. Various processing methodologies such as clustering and antenna decoupling algorithms are also presented.

Autoimmunity is a complex trait disease where the environment influences susceptibility to disease by unclear mechanisms. T cell receptor clustering and signaling at the immune synapse, T cell proliferation, CTLA-4 endocytosis, T H 1 differentiation, and autoimmunity are negatively regulated by ␤1,6GlcNAc-branched N-glycans attached to cell surface glycoproteins. ␤1,6GlcNAc-branched N-glycan expression in T cells is dependent on metabolite supply to UDP-GlcNAc biosynthesis (hexosamine pathway) and in turn to Golgi N-acetylglucosaminyltransferases Mgat1, -2, -4, and -5. In Jurkat T cells, ␤1,6Glc-NAc-branching in N-glycans is stimulated by metabolites supplying the hexosamine pathway including glucose, GlcNAc, acetoacetate, glutamine, ammonia, or uridine but not by control metabolites mannosamine, galactose, mannose, succinate, or pyruvate. Hexosamine supplementation in vitro and in vivo also increases ␤1,6GlcNAc-branched N-glycans in naïve mouse T cells and suppresses T cell receptor signaling, T cell proliferation, CTLA-4 endocytosis, T H 1 differentiation, experimental autoimmune encephalomyelitis, and autoimmune diabetes in non-obese diabetic mice. Our results indicate that metabolite flux through the hexosamine and N-glycan pathways conditionally regulates autoimmunity by modulating multiple T cell functionalities downstream of ␤1,6GlcNAc-branched N-glycans. This suggests metabolic therapy as a potential treatment for autoimmune disease.Complex trait diseases such as autoimmunity are determined by poorly understood genetic and environmental interactions. The T cell-mediated autoimmune diseases multiple sclerosis (MS) 3 and type 1 diabetes exemplify this problem, where identical twins of Northern European descent are discordant ϳ60 -70% of the time despite displaying an ϳ150 -300 times higher risk than the general population prevalence of ϳ0.1 and ϳ0.4%, respectively (1, 2). Genetic-environmental interactions have been established between disease-associated major histocompatibility complex haplotypes and specific pathogen peptides that mimic disease self antigens (3, 4). The prevalence of MS and type 1 diabetes changes along north-south gradients, implicating ultraviolet light exposure and production of vitamin D3 in the skin (5-7), a hormone known to negatively regulate T cell function, the MS animal model experimental autoimmune encephalomyelitis (EAE), and spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse (5, 8 -11). However, molecular mechanisms for genetic-environmental interactions are poorly understood.Salvage of glucosamine by the hexosamine pathway to UDPGlcNAc is reported to suppress T cell function and EAE in mice by an unknown mechanism (12, 13). De novo biosynthesis of UDP-GlcNAc by the hexosamine pathway utilizes glucose, acetyl-CoA, glutamine, and UTP (see Fig. 1), key allosteric regulators of basic metabolism, suggesting regulation of UDP-GlcNAc supply is integrated with down-stream pathways requiring this sugar-nucleotide. In this regard, the Golgi pathway to ␤1,6Glc-NAc-b...

How environmental factors combine with genetic risk at the molecular level to promote complex trait diseases such as multiple sclerosis (MS) is largely unknown. In mice, N-glycan branching by the Golgi enzymes Mgat1 and/or Mgat5 prevents T cell hyperactivity, cytotoxic T-lymphocyte antigen 4 (CTLA-4) endocytosis, spontaneous inflammatory demyelination and neurodegeneration, the latter pathologies characteristic of MS. Here we show that MS risk modulators converge to alter N-glycosylation and/or CTLA-4 surface retention conditional on metabolism and vitamin D3, including genetic variants in interleukin-7 receptor-α (IL7RA*C), interleukin-2 receptor-α (IL2RA*T), MGAT1 (IVAVT−T) and CTLA-4 (Thr17Ala). Downregulation of Mgat1 by IL7RA*C and IL2RA*T is opposed by MGAT1 (IVAVT−T) and vitamin D3, optimizing branching and mitigating MS risk when combined with enhanced CTLA-4 N-glycosylation by CTLA-4 Thr17. Our data suggest a molecular mechanism in MS whereby multiple environmental and genetic inputs lead to dysregulation of a final common pathway, namely N-glycosylation.

Acquisition of the arterial and haemogenic endothelium fates concurrently occur in the aorta–gonad–mesonephros (AGM) region prior to haematopoietic stem cell (HSC) generation. The arterial programme depends on Dll4 and the haemogenic endothelium/HSC on Jag1-mediated Notch1 signalling. How Notch1 distinguishes and executes these different programmes in response to particular ligands is poorly understood. By using two Notch1 activation trap mouse models with different sensitivity, here we show that arterial endothelial cells and HSCs originate from distinct precursors, characterized by different Notch1 signal strengths. Microarray analysis on AGM subpopulations demonstrates that the Jag1 ligand stimulates low Notch strength, inhibits the endothelial programme and is permissive for HSC specification. In the absence of Jag1, endothelial cells experience high Dll4-induced Notch activity and select the endothelial programme, thus precluding HSC formation. Interference with the Dll4 signal by ligand-specific blocking antibodies is sufficient to inhibit the endothelial programme and favour specification of the haematopoietic lineage.

Multiple sclerosis (MS) is characterized by inflammatory demyelination of axons and neurodegeneration, the latter inadequately modeled in experimental autoimmune encephalomyelitis (EAE). Susceptibility of inbred mouse strains to EAE is in part determined by major histocompatibility complex haplotype; however, other molecular mechanisms remain elusive. Galectins bind GlcNAc-branched N-glycans attached to surface glycoproteins, forming a molecular lattice that restricts lateral movement and endocytosis of glycoproteins. GlcNAc branching negatively regulates T cell activity and autoimmunity, and when absent in neurons, induces apoptosis in vivo in young adult mice. We find that EAE susceptible mouse strains PL/J, SJL, and NOD have reduced GlcNAc branching. PL/J mice display the lowest levels, partial deficiencies in N-acetylglucosaminyltransferase I, II, and V (i.e. Mgat1, -2, and -5), T cell hyperactivity and spontaneous late onset inflammatory demyelination and neurodegeneration; phenotypes markedly enhanced by Mgat5 ؉/؊ and Mgat5 ؊/؊ backgrounds in a gene dose-dependent manner. Spontaneous disease is transferable and characterized by progressive paralysis, tremor, dystonia, neuronophagia, and axonal damage in both demyelinated lesions and normal white matter, phenocopying progressive MS. Our data identify hypomorphic Golgi processing as an inherited trait that determines susceptibility to EAE, provides a unique spontaneous model of MS, and suggests GlcNAc-branching deficiency may promote T cell-mediated demyelination and neurodegeneration in MS.Relapsing remitting multiple sclerosis is characterized by inflammatory destruction of the myelin sheath surrounding axons in the central nervous system (CNS), 3 producing relapsing and remitting attacks of neurological dysfunction (1). This is commonly followed by a secondary progressive neurodegenerative phase distinguished by axonal damage and neuronal loss (1). Primary progressive MS is similar to secondary progressive disease but lacks the initial relapsing-remitting phase. However, recent investigations have demonstrated that gray matter involvement and axonal damage in otherwise normal appearing white matter are present at the onset of relapsing remitting multiple sclerosis (2, 3). This indicates neurodegeneration is an early and prominent feature of disease and questions the interpretation that MS is only a T cell-mediated demyelinating disease. Experimental autoimmune encephalomyelitis (EAE) is a useful model of T cell-dependent inflammatory demyelination, but fails to properly address the neurodegenerative phenotype of MS. MS is characterized by adult onset and partially familial relationships, indicating complex interactions between environmental and genetic factors in disease pathogenesis (4). Whole genome screens have identified a number of candidate loci associated with MS (5) and EAE (6, 7), but non-MHC genes that strongly promote disease have yet to be described. This is despite long standing observations that T cell dysfunction is critical to development ...

Summary:  The germinal center (GC) is a unique histological structure found in peripheral lymphoid organs. GCs provide an important source of humoral immunity by generating high affinity antibodies against a pathogen. The GC response is tightly regulated during clonal expansion, immunoglobulin modification, and affinity maturation, whereas its deregulation has a detrimental effect on immune function, leading to development of diseases, such as lymphoma and autoimmunity. LRF (lymphoma/leukemia‐related factor), encoded by the ZBTB7A gene, is a transcriptional repressor belonging to the POK (POZ and Krüppel)/ZBTB (zing finger and BTB) protein family. LRF was originally identified as a PLZF (promyelocytic leukemia zinc finger) homolog that physically interacts with BCL6 (B‐cell lymphoma 6), whose expression is required for GC formation and associated with non‐Hodgkin’s lymphoma. Recently, our group demonstrated that LRF plays critical roles in regulating lymphoid lineage commitment, mature B‐cell development, and the GC response via distinct mechanisms. Herein, we review POK/ZBTB protein function in lymphoid development, with particular emphasis on the role of LRF in GC B cells.

Soft microfluidic systems that capture, store, and perform biomarker analysis of microliter volumes of sweat, in situ, as it emerges from the surface of the skin, represent an emerging class of wearable technology with powerful capabilities that complement those of traditional biophysical sensing devices. Recent work establishes applications in the real-time characterization of sweat dynamics and sweat chemistry in the context of sports performance and healthcare diagnostics. This paper presents a collection of advances in biochemical sensors and microfluidic designs that support multimodal operation in the monitoring of physiological signatures directly correlated to physical and mental stresses. These wireless, battery-free, skin-interfaced devices combine lateral flow immunoassays for cortisol, fluorometric assays for glucose and ascorbic acid (vitamin C), and digital tracking of skin galvanic responses. Systematic benchtop evaluations and field studies on human subjects highlight the key features of this platform for the continuous, noninvasive monitoring of biochemical and biophysical correlates of the stress state.

Future mobile communications systems are likely to be very different to those of today with new service innovations driven by increasing data traffic demand, increasing processing power of smart devices and new innovative applications. To meet these service demands the telecommunications industry is converging on a common set of 5G requirements which includes network speeds as high as 10 Gbps, cell edge rate greater than 100 Mbps, and latency of less than 1 msec. To reach these 5G requirements the industry is looking at new spectrum bands in the range up to 100 GHz where there is spectrum availability for wide bandwidth channels. For the development of new 5G systems to operate in bands up to 100 GHz there is a need for accurate radio propagation models which are not addressed by existing channel models developed for bands below 6 GHz. This paper presents a preliminary overview of the 5G channel models for bands up to 100 GHz in indoor offices and shopping malls, derived from extensive measurements across a multitude of bands. These studies have found some extensibility of the existing 3GPP models (e.g. 3GPP TR36.873) to the higher frequency bands up to 100 GHz. The measurements indicate that the smaller wavelengths introduce an increased sensitivity of the propagation models to the scale of the environment and show some frequency dependence of the path loss as well as increased occurrence of blockage. Further, the penetration loss is highly dependent on the material and tends to increase with frequency. The small-scale characteristics of the channel such as delay spread and angular spread and the multipath richness is somewhat similar over the frequency range, which is encouraging for extending the existing 3GPP models to the wider frequency range. Further work will be carried out to complete these models, but this paper presents the first steps for an initial basis for the model development.