An improved reversed miller compensation technique for three-stage CMOS OTAs with double pole-zero cancellation and almost single-pole frequency response

This paper presents an improved reversed nested Miller compensation technique exploiting a single additional feed-forward stage to obtain double pole-zero cancellation and ideally single-pole behavior, in a three-stage Miller amplifier. The approach allows designing a three-stage operational transconductance amplifier (OTA) with one dominant pole and two (ideally) mutually cancelling pole-zero doublets. We demonstrate the robustness of the proposed cancellation technique, showing that it is not significantly influenced by process and temperature variations. The proposed design equations allow setting the unity-gain frequency of the amplifier and the complex poles' resonance frequency and quality factor. We introduce the notion of bandwidth efficiency to quantify the OTA performance with respect to a telescopic cascode OTA for given load capacitance and power consumption constraints and demonstrate analytically that the proposed approach allows a bandwidth efficiency that can ideally approach 100%. A CMOS implementation of the proposed compensation technique is provided, in which a current reuse scheme is used to reduce the total current consumption. The OTA has been designed using a 130-nm CMOS process by STMicroelectronics and achieves a DC gain larger than 120 dB, with almost single-pole frequency response. Monte Carlo simulations have been performed to show the robustness of the proposed approach to process, voltage, and temperature (PVT) variations and mismatches

10-GHz fully differential Sallen–Key lowpass biquad filters in 55nm SiGe BICMOS technology

Multi-GHz lowpass filters are key components for many RF applications and are required for the implementation of integrated high-speed analog-to-digital and digital-to-analog converters and optical communication systems. In the last two decades, integrated filters in the Multi-GHz range have been implemented using III-V or SiGe technologies. In all cases in which the size of passive components is a concern, inductorless designs are preferred. Furthermore, due to the recent development of high-speed and high-resolution data converters, highly linear multi-GHz filters are required more and more. Classical open loop topologies are not able to achieve high linearity, and closed loop filters are preferred in all applications where linearity is a key requirement. In this work, we present a fully differential BiCMOS implementation of the classical Sallen Key filter, which is able to operate up to about 10 GHz by exploiting both the bipolar and MOS transistors of a commercial 55-nm BiCMOS technology. The layout of the biquad filter has been implemented, and the results of post-layout simulations are reported. The biquad stage exhibits excellent SFDR (64 dB) and dynamic range (about 50 dB) due to the closed loop operation, and good power efficiency (0.94 pW/Hz/pole) with respect to comparable active inductorless lowpass filters reported in the literature. Moreover, unlike other filters, it exploits the different active devices offered by commercial SiGe BiCMOS technologies. Parametric and Monte Carlo simulations are also included to assess the robustness of the proposed biquad filter against PVT and mismatch variations

An ultra-low-voltage class-AB OTA exploiting local CMFB and body-to-gate interface

In this work a novel bulk-driven (BD) ultra-low-voltage (ULV) class-AB operational transconductance amplifier (OTA) which exploits local common mode feedback (LCMFB) strategies to enhance performance and robustness against process, voltage and temperature (PVT) variations has been proposed. The amplifier exploits body-to-gate (B2G) interface to increase the slew rate and attain class-AB behaviour, whereas two pseudo-resistors have been employed to increase the common mode rejection ratio (CMRR). The architecture has been extensively tested through Monte Carlo and PVT simulations, results show that the amplifier is very robust in terms of gain-bandwidth-product (GBW), power consumption and slew rate. A wide comparison against state-of-the-art has pointed out that best small-signal figures of merit are attained and good large-signal performance is guaranteed, also when worst-case slew rate is considered

Methods for Model Complexity Reduction for the Nonlinear Calibration of Amplifiers Using Volterra Kernels

Volterra models allow modeling nonlinear dynamical systems, even though they require the estimation of a large number of parameters and have, consequently, potentially large computational costs. The pruning of Volterra models is thus of fundamental importance to reduce the computational costs of nonlinear calibration, and improve stability and speed, while preserving accuracy. Several techniques (LASSO, DOMP and OBS) and their variants (WLASSO and OBD) are compared in this paper for the experimental calibration of an IF amplifier. The results show that Volterra models can be simplified, yielding models that are 4–5 times sparser, with a limited impact on accuracy. About 6 dB of improved Error Vector Magnitude (EVM) is obtained, improving the dynamic range of the amplifiers. The Symbol Error Rate (SER) is greatly reduced by calibration at a large input power, and pruning reduces the model complexity without hindering SER. Hence, pruning allows improving the dynamic range of the amplifier, with almost an order of magnitude reduction in model complexity. We propose the OBS technique, used in the neural network field, in conjunction with the better known DOMP technique, to prune the model with the best accuracy. The simulations show, in fact, that the OBS and DOMP techniques outperform the others, and OBD, LASSO and WLASSO are, in turn, less efficient. A methodology for pruning in the complex domain is described, based on the Frisch–Waugh–Lovell (FWL) theorem, to separate the linear and nonlinear sections of the model. This is essential because linear models are used for equalization and cannot be pruned to preserve model generality vis-a-vis channel variations, whereas nonlinear models must be pruned as much as possible to minimize the computational overhead. This methodology can be extended to models other than the Volterra one, as the only conditions we impose on the nonlinear model are that it is feedforward and linear in the parameters

Polarized monocyte response to cytokine stimulation

BACKGROUND: Mononuclear phagocytes (MPs) stand at the crossroads between the induction of acute inflammation to recruit and activate immune effector cells and the downmodulation of the inflammatory process to contain collateral damage. This decision is extensively modulated by the cytokine microenvironment, which includes a broad array of cytokines whose direct effect on MPs remains largely unexplored. Therefore, we tested whether polarized responses of MPs to pathogens are related to the influence of selected cytokines or represent a mandatory molecular switch through which most cytokines operate. RESULTS: Circulating CD14+ MPs were exposed to bacterial lipopolysaccharide (LPS) followed by exposure to an array of cytokines, chemokines and soluble factors involved in the immune response. Gene expression was studied by global transcript analysis. Two main classes of cytokines were identified that induced a classical or an alternative pathway of MP activation. Expression of genes affected by NFkappaB activation was most predictive of the two main classes, suggesting that this pathway is a fundamental target of cytokine regulation. As LPS itself induces a classical type of activation, the most dramatic modulation was observed toward the alternative pathway, suggesting that a broad array of cytokines may counteract the pro-inflammatory effects of bacterial components. CONCLUSIONS: This analysis is directly informative of the primary effect of individual cytokines on the early stages of LPS stimulation and, therefore, may be most informative of the way MP maturation may be polarized at the early stages of the immune response

A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis

The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10–7 and 1.16 x 10–6], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors

Cancer treatment: the combination of vaccination with other therapies

Harnessing of the immune system by the development of ‘therapeutic’ vaccines, for the battle against cancer has been the focus of tremendous research efforts over the past two decades. As an illustration of the impressive amounts of data gathered over the past years, numerous antigens expressed on the surface of cancer cells, have been characterized. To this end, recent years research has focussed on characterization of antigens that play an important role for the growth and survival of cancer cells. Anti-apoptotic molecules like survivin that enhance the survival of cancer cells and facilitate their escape from cytotoxic therapies represent prime vaccination candidates. The characterization of a high number of tumor antigens allow the concurrent or serial immunological targeting of different proteins associated with such cancer traits. Moreover, while vaccination in itself is a promising new approach to fight cancer, the combination with additional therapy could create a number of synergistic effects. Herein we discuss the possibilities and prospects of vaccination when combined with other treatments. In this regard, cell death upon drug exposure may be immunogenic or non-immunogenic depending on the specific chemotherapeutics. Also, chemotherapy represents one of several options available for clearance of CD4+ Foxp3+ regulatory T cells. Moreover, therapies based on monoclonal antibodies may have synergistic potential in combination with vaccination, both when used for targeting of tumor cells and endothelial cells. The efficacy of therapeutic vaccination against cancer will over the next few years be studied in settings taking advantage of strategies in which vaccination is combined with other treatment modalities. These combinations should be based on current knowledge not only regarding the biology of the cancer cell per se, but also considering how treatment may influence the malignant cell population as well as the immune system

Diversity and Recognition Efficiency of T Cell Responses to Cancer

BACKGROUND: Melanoma patients vaccinated with tumor-associated antigens frequently develop measurable peptide-specific CD8+ T cell responses; however, such responses often do not confer clinical benefit. Understanding why vaccine-elicited responses are beneficial in some patients but not in others will be important to improve targeted cancer immunotherapies. METHODS AND FINDINGS: We analyzed peptide-specific CD8+ T cell responses in detail, by generating and characterizing over 200 cytotoxic T lymphocyte clones derived from T cell responses to heteroclitic peptide vaccination, and compared these responses to endogenous anti-tumor T cell responses elicited naturally (a heteroclitic peptide is a modification of a native peptide sequence involving substitution of an amino acid at an anchor residue to enhance the immunogenicity of the peptide). We found that vaccine-elicited T cells are diverse in T cell receptor variable chain beta expression and exhibit a different recognition profile for heteroclitic versus native peptide. In particular, vaccine-elicited T cells respond to native peptide with predominantly low recognition efficiency—a measure of the sensitivity of a T cell to different cognate peptide concentrations for stimulation—and, as a result, are inefficient in tumor lysis. In contrast, endogenous tumor-associated-antigen-specific T cells show a predominantly high recognition efficiency for native peptide and efficiently lyse tumor targets. CONCLUSIONS: These results suggest that factors that shape the peptide-specific T cell repertoire after vaccination may be different from those that affect the endogenous response. Furthermore, our findings suggest that current heteroclitic peptide vaccination protocols drive expansion of peptide-specific T cells with a diverse range of recognition efficiencies, a significant proportion of which are unable to respond to melanoma cells. Therefore, it is critical that the recognition efficiency of vaccine-elicited T cells be measured, with the goal of advancing those modalities that elicit T cells with the greatest potential of tumor reactivity

Permissivity of the NCI-60 cancer cell lines to oncolytic Vaccinia Virus GLV-1h68

<p>Abstract</p> <p>Background</p> <p>Oncolytic viral therapy represents an alternative therapeutic strategy for the treatment of cancer. We previously described GLV-1h68, a modified Vaccinia Virus with exclusive tropism for tumor cells, and we observed a cell line-specific relationship between the ability of GLV-1h68 to replicate in vitro and its ability to colonize and eliminate tumor in vivo.</p> <p>Methods</p> <p>In the current study we surveyed the in vitro permissivity to GLV-1h68 replication of the NCI-60 panel of cell lines. Selected cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain. In order to identify correlates of permissity to viral infection, we measured transcriptional profiles of the cell lines prior infection.</p> <p>Results</p> <p>We observed highly heterogeneous permissivity to VACV infection amongst the cell lines. The heterogeneity of permissivity was independent of tissue with the exception of B cell derivation. Cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain and a significant correlation was found suggesting a common permissive phenotype. While no clear transcriptional pattern could be identified as predictor of permissivity to infection, some associations were observed suggesting multifactorial basis permissivity to viral infection.</p> <p>Conclusions</p> <p>Our findings have implications for the design of oncolytic therapies for cancer and offer insights into the nature of permissivity of tumor cells to viral infection.</p

Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72

A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for similar to 40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for similar to 60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis