HiJAKing innate lymphoid cells?

The family of innate lymphoid cells (ILCs) consists of a heterogeneous group of cytokine-producing cells that have features in common with adaptive T helper (Th) cells. Cytokines acting through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways are key players in both Th and ILC biology. Observations in animal models, supported by evidence from humans, have highlighted the importance of the downstream events evoked by the cytokines that signal through the common IL-2 γ-chain receptor. Similarly, it is reasonable to assume that therapeutic targeting of this signaling cascade will also modulate ILC effector function in disease. Since a major limitation of gene knockout studies in mice is the complete loss of ILC populations, including NK cells, we believe that an attractive, alternative, strategy would be to study the role of cytokine signaling in the regulation of ILC function by pharmacological manipulation of these pathways instead. Here, we discuss the potential of JAK inhibitors as a drug class to elucidate mechanisms underlying ILC biology and to inform the design of new therapeutic strategies for inflammatory and autoimmune disorders

Janus kinases to jakinibs : from basic insights to clinical practice

Cytokines are critical mediators of diverse immune and inflammatory diseases. Targeting cytokines and cytokine receptors with biologics has revolutionized the treatment of many of these diseases, but targeting intracellular signalling with Janus kinase (JAK) inhibitors (jakinibs) now represents a major new therapeutic advance. We are still in the first decade since these drugs were approved and there is still much to be learned about the mechanisms of action of these drugs and the practical use of these agents. Herein we will review cytokines that do, and just as importantly, do not signal by JAKs, as well as explain how this relates to both efficacy and side effects in various diseases. We will review new, next-generation selective jakinibs, as well as the prospects and challenges ahead in targeting JAKs.Peer reviewe

Single-Chip FPGA Azimuth Pre-Filter for SAR

A field-programmable gate array (FPGA) on a single lightweight, low-power integrated-circuit chip has been developed to implement an azimuth pre-filter (AzPF) for a synthetic-aperture radar (SAR) system. The AzPF is needed to enable more efficient use of data-transmission and data-processing resources: In broad terms, the AzPF reduces the volume of SAR data by effectively reducing the azimuth resolution, without loss of range resolution, during times when end users are willing to accept lower azimuth resolution as the price of rapid access to SAR imagery. The data-reduction factor is selectable at a decimation factor, M, of 2, 4, 8, 16, or 32 so that users can trade resolution against processing and transmission delays. In principle, azimuth filtering could be performed in the frequency domain by use of fast-Fourier-transform processors. However, in the AzPF, azimuth filtering is performed in the time domain by use of finite-impulse-response filters. The reason for choosing the time-domain approach over the frequency-domain approach is that the time-domain approach demands less memory and a lower memory-access rate. The AzPF operates on the raw digitized SAR data. The AzPF includes a digital in-phase/quadrature (I/Q) demodulator. In general, an I/Q demodulator effects a complex down-conversion of its input signal followed by low-pass filtering, which eliminates undesired sidebands. In the AzPF case, the I/Q demodulator takes offset video range echo data to the complex baseband domain, ensuring preservation of signal phase through the azimuth pre-filtering process. In general, in an SAR I/Q demodulator, the intermediate frequency (fI) is chosen to be a quarter of the range-sampling frequency and the pulse-repetition frequency (fPR) is chosen to be a multiple of fI. The AzPF also includes a polyphase spatial-domain pre-filter comprising four weighted integrate-and-dump filters with programmable decimation factors and overlapping phases. To prevent aliasing of signals, the bandwidth of the AzPF is made 80 percent of fPR/M. The choice of four as the number of overlapping phases is justified by prior research in which it was shown that a filter of length 4M can effect an acceptable transfer function. The figure depicts prototype hardware comprising the AzPF and ancillary electronic circuits. The hardware was found to satisfy performance requirements in real-time tests at a sampling rate of 100 MHz

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The maternal microbiome during pregnancy and allergic disease in the offspring

There is substantial epidemiological and mechanistic evidence that the increase in allergic disease and asthma in many parts of the world in part relates to changes in microbial exposures and diet acting via the composition and metabolic products of the intestinal microbiome. The majority of research in this field has focused on the gut microbiome during infancy, but it is increasingly clear that the maternal microbiome during pregnancy also has a key role in preventing an allergy-prone immune phenotype in the offspring. The mechanisms by which the maternal microbiome influences the developing fetal immune system include alignment between the maternal and infant regulatory immune status and transplacental passage of microbial metabolites and IgG. Interplay between microbial stimulatory factors such as lipopolysaccharides and regulatory factors such as short-chain fatty acids may also influence on fetal immune development. However, our understanding of these pathways is at an early stage and further mechanistic studies are needed. There are also no data from human studies relating the composition and metabolic activity of the maternal microbiome during pregnancy to the offspring's immune status at birth and risk of allergic disease. Improved knowledge of these pathways may inform novel strategies for tackling the increase in allergic disorders in the modern world