Sarnoff Cardiovascular Research Foundation

To efficiently distribute blood flow to cardiac muscle, the coronary artery tree must follow a specific branching pattern over the heart. How this pattern arises in humans is unknown due to the limitations of studying human heart development. Here, we leveraged a natural variation of coronary artery anatomy, known as coronary dominance, in genetic association studies to identify the first known driver of human coronary developmental patterning. Coronary dominance refers to whether the right, left, or both coronary arteries branch over the posterior left ventricle, but whether this variability is heritable and how it would be genetically regulated was completely unknown. By conducting the first large-scale, multi-ancestry genome-wide association study (GWAS) of coronary dominance in 61,043 participants of the VA Million Veteran Program, we observed moderate heritability (27.7%) with ten loci reaching genome wide significance. An exceptionally strong association mapped DNA variants to a non-coding region near the chemokine CXCL12 in both European and African ancestries, which overlapped with variants associated with coronary artery disease. Genomic analyses predicted these variants to impact CXCL12 levels, and imaging revealed dominance to develop during fetal life coincident with CXCL12 expression. Reducing Cxcl12 in mice to model the human genetics altered septal artery dominance patterns and caused coronary branches to develop away from Cxcl12 expression domains. Cxcl12 heterozygosity did not compromise overall artery coverage as seen with full deletion, but instead changed artery patterning, reminiscent of the human scenario. Together, our data support CXCL12 as a critical determinant of human coronary artery growth and patterning and lay a foundation for the utilization of developmental pathways to guide future precision 'medical revascularization' therapeutics.

Background: Lower body mass is thought to enhance athletic performance. We explored the relationship between BMI and aerobic fitness in athletic younger and older men and women. Methods: We examined 2224 patients (805 women, 1419 men) ages 17 through 91, referred to the Cardiovascular Performance Program at Massachusetts General Hospital between 2011 and 2019. Cardiorespiratory fitness (CRF; Peak V0 2 ) was assessed and expressed as %- predicted peak V0 2 , using the equation of Jones to adjust for age, height, and weight. Associations were evaluated using linear regression. Results: Mean peak VO 2 was 34.3±14.1 mL/kg/min, and median %-predicted VO 2 was 105%. We observed an inverse association between BMI and CRF in adults over 30 years old ( B = -0.043, p = 3.3x10 -33 for men, B = -0.051, p = 1.6 x 10 -13 for women) (Fig 1a) and men under 30 ( B = -0.025, p = 0.005) (Fig 1b). No linear association was found in younger women ages 17 - 29 ( B = -0.0078, p = 0.38) (Fig 1b). In contrast, a quadratic model disclosed a direct relationship at lower BMI and an inverse relationship at higher BMI (Fig 1c). An examination of high fitness young adults (defined as having %-predicted VO 2 ≥ 120%) demonstrates that fit women have mean BMI’s of 23.15 ± 2.69 (Fig 1d). Conclusion: These data highlight that BMI and fitness in younger aerobically fit women do not follow a simple linear relationship but one that is parabolic in nature. High fitness in young women occurs with highest density in the upper strata of the WHO and NIH-defined range of healthy BMI. These data support a deemphasis of weight loss generally and BMI specifically to enhance aerobic performance in athletic young women.

Background. We have found that without immunosuppression, life-sustaining, full MHC-mismatched mouse kidney allografts were spontaneously accepted in the DBA/2 to B6 strain combination. Using B6.Foxp3DTR mice, we have shown that Foxp3+ cells are necessary to maintain spontaneous kidney allograft tolerance. Pathological analyses of accepted kidney allografts demonstrated unique, Tregrich organized lymphoid structures (TOLS), which were rich in Foxp3+ Tregs and plasmacytoid dendritic cells (pDCs), and which were distinct from tertiary lymphoid structures. Methods. To test whether pDCs could promote Treg production, we isolated pDCs from DBA mouse bone marrow and cultured them in vitro with naïve CD4<sup style=“font-family: ‘Times New Roman', serif;”>+[/sup] CD25<sup style=“font-family: ‘Times New Roman', serif;”>- [/sup]T cells from B6 mouse spleen in the presence of IL-2 and TGFβ. We then analyzed these cells for suppressive capacity by MLR utilizing CFSE dilution in responding CD4+CD25- B6 T cells. Results. We observed an increased expression of Foxp3 in the co-cultured T cells. Addition of Foxp3+ T cell/pDC cultures also suppressed proliferation in vitro when CFSE labeled naïve B6 T cells were stimulated by nonspecific anti-CD3/anti-CD28 beads (mean 95.8% vs 6.0% proliferating cells, p<.001) or irradiated allogeneic stimulators in sensitized mice (mean 13.8% vs 3.75% proliferating cells, p<.001). This suppression was greater than that induced by CD4+CD25+ Foxp3+ nTregs isolated from B6 mice and cultured in an equal ratio to responder T cells after bead (mean 67.8% vs 6.0% proliferating cells, p<.001) or allogeneic (mean 7.7% vs 3.75% proliferating cells, p<.02) stimulus. Adoptive transfer of the induced murine Foxp3<sup style=“font-family: ‘Times New Roman', serif;”>+[/sup] T cell and pDC mixture into B6 recipients 2 weeks prior to heterotopic DBA/2 heart transplantation resulted in prolongation of allograft survival (MST =11 days, n=6) compared to vehicle treated controls (MST = 6 days, n=6) or compared to pDCs coinjected with co-cultured B6 naïve T cells that were non-induced (no IL-2/TGFβ) (n=3, MST=7 days) (p<.002). Conclusions. Allogeneic pDCs can promote the generation of highly suppressive Foxp3+ Tregs in vitro which have the ability to prolong vascularized allograft tolerance in vivo without any further treatment.

Recent studies suggest that the radiative conversion efficiency of mid-infrared semiconductor devices is limited by non-radiative Auger mechanisms. Band structure engineering techniques, such as the introduction of strain or the use of type-II band offset materials, have been shown to reduce the effect of Auger recombination. Results from light emitting diodes (LEDs) with an active region consisting of ten InAs/GaInSb/InAs/AlGaAsSb type-II ‘W’ quantum wells grown by molecular beam epitaxy (MBE) on GaSb substrates are described. At room temperature, the device was characterised by a slope efficiency of 98 µW/A at low currents, which dropped at higher currents due to heating. This corresponded to an internal efficiency of approximately 2.6%.

A 2100 line-per-inch, active matrix liquid crystal display technology has been developed. Functional displays were produced and demonstrated with contrast ratios of up to 50:1. The achievement of a 12 micrometers pixel pitch results in only a 1.5 inch diagonal for the 2560 by 2048 pixel array of 5.24 million pixels. Display drive electronics integrated into the periphery areas around the pixel array include row addressing, column select/video data loading, and clock circuits. External electronics requirements are reduced and the display connector contains only video, clock and power lines. The active matrix TFT's and peripheral circuits contain over 5.3 million transistors, the complexity of a large integrated circuit. Six display circuits were fabricated on each 6 inch Silicon-On-Insulator wafers using CMOS IC processes. The single crystal silicon circuits readily achieve the high speeds required to drive these large pixel arrays at a 60 Hz frame rate. The thin x-Si layer containing the display circuits was transferred from the silicon wafer to glass in the manufacturing process. This approach leverages mature wafer-based IC processing for display manufacturing.

Abstract New observations are presented on the emission of electrons from n-type boron nitride (BN) cold cathode films. These carbon-doped BN films demonstrate a significant improvement in the electron emission current, on the order of 1 to 3 orders of magnitude, as a function of the extraction field for many different materials and morphologies.These BN cold cathodes have yielded stable DC currents in excess of 4 mA at an extraction field of approximately 30 V/μm.

Field deployable, high frame rate visible CCD camera systems have been developed to support the Test and Evaluation activities at the White Sands Missile Range. These visible cameras are designed around a Sarnoff 1024 X 1024 pixel, backside illuminated CCD with a 32-port, split-frame transfer architecture. The cameras exploit this architecture to provide selectable modes from a 30 Hz frame rate at 1024 X 1024 pixels to a 300 Hz frame rate with 1024 X 512 pixels (2:1 vertical binning). The cameras are configured with a 500 mm, f/4 lens, and a Ferro-electric liquid crystal electro-optic shutter, to provide variable integration times from 0.5 to 32 msec. Video outputs provided are RS170 analog video in a reduced 512 X 480 pixel format, and 12-bit full resolution digital video data stream provided through a high speed serial/parallel digital coaxial interface. At a frame rate of 300 frames per second, these cameras deliver video data at an average rate of 1.9 Gbits/sec, and a burst rate of 2.8 Gbits/sec, with the capability of reaching an average 12 bit digital data rate of 3.8 Gbits/sec when higher frame rate imagers become available.

We describe a novel technique for displaying video in which image frames are continually accumulated within the display devices to form an evolving mosaic. This `video mosaic' effectively extends the field of view and resolution of the source camera, and can aid in tasks such as surveillance and teleoperation.

Microcalcifications are important cues used by radiologists for early detection in breast cancer. Individually, microcalcifications are difficult to detect, and often contextual information (e.g. clustering, location relative to ducts) can be exploited to aid in their detection. We have developed an algorithm for constructing a hierarchical pyramid/neural network (HPNN) architecture to automatically learn context information for detection. To test the HPNN we first examined if the hierarchical architecture improves detection of individual microcalcifications and if context is in fact extracted by the network hierarchy. We compared the performance of our hierarchical architecture versus a single neural network receiving input from all resolutions of a feature pyramid. Receiver operator characteristic (ROC) analysis shows that the hierarchical architecture reduces false positives by a factor of two. We examined hidden units at various levels of the processing hierarchy and found what appears to be representations of ductal location. We next investigated the utility of the HPNN if integrated as part of a complete computer-aided diagnosis (CAD) system for microcalcification detection, such as that being developed at the University of Chicago. Using ROC analysis, we tested the HPNN's ability to eliminate false positive regions of interest generated by the computer, comparing its performance to the neural network currently used in the Chicago system. The HPNN achieves an area under the ROC curve of Az equal to .94 and a false positive fraction of FPF equal to .21 at TPF equals 1.0. This is in comparison to the results reported for the Chicago network; Az equal to .91, FPF equal to .43 at TPF equal to 1.0. These differences are statistically significant. We conclude that the HPNN algorithm is able to utilize contextual information for improving microcalcifications detection and potentially reduce the false positive rates in CAD systems.

In this paper we present 3D registration techniques for detecting breast cancer lesions based on differences between the high spatial resolution 'pre' and 'post' contrast administration MR breast scans. We also present registration techniques for detecting lesions based on the time course of enhancement after administration of the contrast agent based on changes in the low spatial resolution, high temporal resolution, dynamic MR data taken during the absorption of the contrast agent. Alignment of the 'pre' and 'post' MR data and of the dynamic MR images is done by a direct optimization technique to estimate a global affine deformation model using a coarse-to-fine control strategy over a 3D pyramid. This global model is followed by a one iteration flow estimation to account for any local non-rigidity. We present results of the registration process and visualization of the different volumes obtained after alignment.