Low-voltage embedded biomedical processor design

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2010.Cataloged from PDF version of thesis.Includes bibliographical references (p. 180-190).Advances in mobile electronics are fueling new possibilities in a variety of applications, one of which is ambulatory medical monitoring with body-worn or implanted sensors. Digital processors on such sensors serve to analyze signals in real-time and extract key features for transmission or storage. To support diverse and evolving applications, the processor should be flexible, and to extend sensor operating lifetime, the processor should be energy-efficient. This thesis focuses on architectures and circuits for low power biomedical signal processing. A general-purpose processor is extended with custom hardware accelerators to reduce the cycle count and energy for common tasks, including FIR and median filtering as well as computing FFTs and mathematical functions. Improvements to classic architectures are proposed to reduce power and improve versatility: an FFT accelerator demonstrates a new control scheme to reduce datapath switching activity, and a modified CORDIC engine features increased input range and decreased quantization error over conventional designs. At the system level, the addition of accelerators increases leakage power and bus loading; strategies to mitigate these costs are analyzed in this thesis. A key strategy for improving energy efficiency is to aggressively scale the power supply voltage according to application performance demands. However, increased sensitivity to variation at low voltages must be mitigated in logic and SRAM design. For logic circuits, a design flow and a hold time verification methodology addressing local variation are proposed and demonstrated in a 65nm microcontroller functioning at 0.3V. For SRAMs, a model for the weak-cell read current is presented for near-V supply voltages, and a self-timed scheme for reducing internal bus glitches is employed with low leakage overhead. The above techniques are demonstrated in a 0.5-1.OV biomedical signal processing platform in 0.13p-Lm CMOS. The use of accelerators for key signal processing enabled greater than 10x energy reduction in two complete EEG and EKG analysis applications, as compared to implementations on a conventional processor.by Joyce Y. S. Kwong.Ph.D

A sub-threshold cell library and methodology

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2006.Includes bibliographical references (p. 97-102).Sub-threshold operation is a compelling approach for energy-constrained applications where speed is of secondary concern, but increased sensitivity to process variation must be mitigated in this regime. With scaling of process technologies, random within-die variation has recently introduced another degree of complexity in circuit design. This thesis proposes approaches to mitigate process variation in sub-threshold circuits through device sizing, topology selection and fault-tolerant architecture. This thesis makes several contributions to a sub-threshold circuit design methodology. A formal analysis of device sizing trade-offs between delay, energy, and variability reveals that while minimum size devices provide lowest energy and delay in sub-threshold, their increased sensitivity to random dopant fluctuation may cause functional errors. A proposed variation-driven design approach enables consistent sizing of logic gates and registers for constant functional yield. A yield constraint imposes energy overhead at low power supply voltages and changes the minimum energy operating point of a circuit.(cont.) The optimal supply and device sizing depend on the topology of the circuit and its energy versus VDD characteristic. The analysis resulted in a 56-cell library in 65nm CMOS, which is incorporated in a computer-aided design flow. A test chip synthesized from this library implements a fault-tolerant FIR filter. Algorithmic error detection enables correction of transient timing errors due to delay variability in sub-threshold, and also allows the system frequency to be set more aggressively for the average case instead of the worst case.by Joyce Y.S. Kwong.S.M

Design of Low-Voltage Digital Building Blocks and ADCs for Energy-Efficient Systems

Increasing number of energy-limited applications continue to drive the demand for designing systems with high energy efficiency. This tutorial covers the main building blocks of a system implementation including digital logic, embedded memories, and analog-to-digital converters and describes the challenges and solutions to designing these blocks for low-voltage operation

Genome-Wide Association Study of Hepatocellular Carcinoma in Southern Chinese Patients with Chronic Hepatitis B Virus Infection

One of the most relevant risk factors for hepatocellular carcinoma (HCC) development is chronic hepatitis B virus (HBV) infection, but only a fraction of chronic HBV carriers develop HCC, indicating that complex interactions among viral, environmental and genetic factors lead to HCC in HBV-infected patients. So far, host genetic factors have incompletely been characterized. Therefore, we performed a genome-wide association (GWA) study in a Southern Chinese cohort consisting of 95 HBV-infected HCC patients (cases) and 97 HBV-infected patients without HCC (controls) using the Illumina Human610-Quad BeadChips. The top single nucleotide polymorphisms (SNPs) were then validated in an independent cohort of 500 cases and 728 controls. 4 SNPs (rs12682266, rs7821974, rs2275959, rs1573266) at chromosome 8p12 showed consistent association in both the GWA and replication phases (ORcombined = 1.31–1.39; pcombined = 2.71×10−5–5.19×10−4; PARcombined = 26–31%). We found a 2.3-kb expressed sequence tag (EST) in the region using in-silico data mining and verified the existence of the full-length EST experimentally. The expression level of the EST was significantly reduced in human HCC tumors in comparison to the corresponding non-tumorous liver tissues (P<0.001). Results from sequence analysis and in-vitro protein translation study suggest that the transcript might function as a long non-coding RNA. In summary, our study suggests that variations at chromosome 8p12 may promote HCC in patients with HBV. Further functional studies of this region may help understand HBV-associated hepatocarcinogenesis

Silicon photonic transmitter for polarization-encoded quantum key distribution

Silicon (Si) photonics is forming a fabless ecosystem, which is enabling low-cost and densely integrated components for optical communications and quantum information. We present a Si optical transmitter for polarization-encoded quantum key distribution (QKD). The chip was fabricated in a standard Si photonic foundry process and integrated together a pulse generator, intensity modulator, variable optical attenuator, and polarization modulator in a 1.3  mm×3  mm1.3  mm×3  mm die area. The devices in the photonic circuit meet the requirements for QKD. The transmitter was used in a proof-of-concept demonstration of the BB84 QKD protocol over a 5 km long fiber link. This work shows the potential of using foundry Si photonics for low-cost, wafer-scale fabricated components for quantum information

Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape

A comprehensive understanding of the regions on HIV-1 envelope trimers targeted by broadly neutralizing antibodies may contribute to rational design of an HIV-1 vaccine. We previously identified a participant in the CAPRISA cohort, CAP248, who developed trimer-specific antibodies capable of neutralizing 60% of heterologous viruses at three years post-infection. Here, we report the isolation by B cell culture of monoclonal antibody CAP248-2B, which targets a novel membrane proximal epitope including elements of gp120 and gp41. Despite low maximum inhibition plateaus, often below 50% inhibitory concentrations, the breadth of CAP248-2B significantly correlated with donor plasma. Site-directed mutagenesis, X-ray crystallography, and negative-stain electron microscopy 3D reconstructions revealed how CAP248-2B recognizes a cleavage-dependent epitope that includes the gp120 C terminus. While this epitope is distinct, it overlapped in parts of gp41 with the epitopes of broadly neutralizing antibodies PGT151, VRC34, 35O22, 3BC315, and 10E8. CAP248-2B has a conformationally variable paratope with an unusually long 19 amino acid light chain third complementarity determining region. Two phenylalanines at the loop apex were predicted by docking and mutagenesis data to interact with the viral membrane. Neutralization by CAP248-2B is not dependent on any single glycan proximal to its epitope, and low neutralization plateaus could not be completely explained by N- or O-linked glycosylation pathway inhibitors, furin co-transfection, or pre-incubation with soluble CD4. Viral escape from CAP248-2B involved a cluster of rare mutations in the gp120-gp41 cleavage sites. Simultaneous introduction of these mutations into heterologous viruses abrogated neutralization by CAP248-2B, but enhanced neutralization sensitivity to 35O22, 4E10, and 10E8 by 10-100-fold. Altogether, this study expands the region of the HIV-1 gp120-gp41 quaternary interface that is a target for broadly neutralizing antibodies and identifies a set of mutations in the gp120 C terminus that exposes the membrane-proximal external region of gp41, with potential utility in HIV vaccine design

Sequence-Signature Optimization Enables Improved Identification of Human HV6-1-Derived Class Antibodies That Neutralize Diverse Influenza A Viruses

Sequence signatures of multidonor broadly neutralizing influenza antibodies can be used to quantify the prevalence of B cells with virus-neutralizing potential to accelerate development of broadly protective vaccine strategies. Antibodies of the same class share similar recognition modes and developmental pathways, and several antibody classes have been identified that neutralize diverse group 1- and group 2-influenza A viruses and have been observed in multiple human donors. One such multidonor antibody class, the HV6-1-derived class, targets the stem region of hemagglutinin with extraordinary neutralization breadth. Here, we use an iterative process to combine informatics, biochemical, and structural analyses to delineate an improved sequence signature for HV6-1-class antibodies. Based on sequence and structure analyses of known HV6-1 class antibodies, we derived a more inclusive signature (version 1), which we used to search for matching B-cell transcripts from published next-generation sequencing datasets of influenza vaccination studies. We expressed selected antibodies, evaluated their function, and identified amino acid-level requirements from which to refine the sequence signature (version 2). The cryo-electron microscopy structure for one of the signature-identified antibodies in complex with hemagglutinin confirmed motif recognition to be similar to known HV6-1-class members, MEDI8852 and 56.a.09, despite differences in recognition-loop length. Threading indicated the refined signature to have increased accuracy, and signature-identified heavy chains, when paired with the light chain of MEDI8852, showed neutralization comparable to the most potent members of the class. Incorporating sequences of additional class members thus enables an improved sequence signature for HV6-1-class antibodies, which can identify class members with increased accuracy