Statistical inference of the generation probability of T-cell receptors from sequence repertoires

Stochastic rearrangement of germline DNA by VDJ recombination is at the origin of immune system diversity. This process is implemented via a series of stochastic molecular events involving gene choices and random nucleotide insertions between, and deletions from, genes. We use large sequence repertoires of the variable CDR3 region of human CD4+ T-cell receptor beta chains to infer the statistical properties of these basic biochemical events. Since any given CDR3 sequence can be produced in multiple ways, the probability distribution of hidden recombination events cannot be inferred directly from the observed sequences; we therefore develop a maximum likelihood inference method to achieve this end. To separate the properties of the molecular rearrangement mechanism from the effects of selection, we focus on non-productive CDR3 sequences in T-cell DNA. We infer the joint distribution of the various generative events that occur when a new T-cell receptor gene is created. We find a rich picture of correlation (and absence thereof), providing insight into the molecular mechanisms involved. The generative event statistics are consistent between individuals, suggesting a universal biochemical process. Our distribution predicts the generation probability of any specific CDR3 sequence by the primitive recombination process, allowing us to quantify the potential diversity of the T-cell repertoire and to understand why some sequences are shared between individuals. We argue that the use of formal statistical inference methods, of the kind presented in this paper, will be essential for quantitative understanding of the generation and evolution of diversity in the adaptive immune system.Comment: 20 pages, including Appendi

Architecture of the Short External Rotator Muscles of the Hip.

BackgroundMuscle architecture, or the arrangement of sarcomeres and fibers within muscles, defines functional capacity. There are limited data that provide an understanding of hip short external rotator muscle architecture. The purpose of this study was thus to characterize the architecture of these small hip muscles.MethodsEight muscles from 10 independent human cadaver hips were used in this study (n = 80 muscles). Architectural measurements were made on pectineus, piriformis, gemelli, obturators, quadratus femoris, and gluteus minimus. Muscle mass, fiber length, sarcomere length, and pennation angle were used to calculate the normalized muscle fiber length, which defines excursion, and physiological cross-sectional area (PCSA), which defines force-producing capacity.ResultsGluteus minimus had the largest PCSA (8.29 cm2) followed by obturator externus (4.54 cm2), whereas superior gemellus had the smallest PCSA (0.68 cm2). Fiber lengths clustered into long (pectineus - 10.38 cm and gluteus minimus - 10.30 cm), moderate (obturator internus - 8.77 cm and externus - 8.04 cm), or short (inferior gemellus - 5.64 and superior gemellus - 4.85). There were no significant differences among muscles in pennation angle which were all nearly zero. When the gemelli and obturators were considered as a single functional unit, their collective PCSA (10.00 cm2) exceeded that of gluteus minimus as a substantial force-producing group.ConclusionsThe key findings are that these muscles have relatively small individual PCSAs, short fiber lengths, and low pennation angles. The large collective PCSA and short fiber lengths of the gemelli and obturators suggest that they primarily play a stabilizing role rather than a joint rotating role

Hole Spin Coherence in a Ge/Si Heterostructure Nanowire

Relaxation and dephasing of hole spins are measured in a gate-defined Ge/Si nanowire double quantum dot using a fast pulsed-gate method and dispersive readout. An inhomogeneous dephasing time $T_2^* \sim 0.18~\mathrm{\mu s}$ exceeds corresponding measurements in III-V semiconductors by more than an order of magnitude, as expected for predominately nuclear-spin-free materials. Dephasing is observed to be exponential in time, indicating the presence of a broadband noise source, rather than Gaussian, previously seen in systems with nuclear-spin-dominated dephasing.Comment: 15 pages, 4 figure

Antilocalization of Coulomb Blockade in a Ge-Si Nanowire

The distribution of Coulomb blockade peak heights as a function of magnetic field is investigated experimentally in a Ge-Si nanowire quantum dot. Strong spin-orbit coupling in this hole-gas system leads to antilocalization of Coulomb blockade peaks, consistent with theory. In particular, the peak height distribution has its maximum away from zero at zero magnetic field, with an average that decreases with increasing field. Magnetoconductance in the open-wire regime places a bound on the spin-orbit length ($l_{so}$ < 20 nm), consistent with values extracted in the Coulomb blockade regime ($l_{so}$ < 25 nm).Comment: Supplementary Information available at http://bit.ly/19pMpd

Imaging a 1-electron InAs quantum dot in an InAs/InP nanowire

Nanowire heterostructures define high-quality few-electron quantum dots for nanoelectronics, spintronics and quantum information processing. We use a cooled scanning probe microscope (SPM) to image and control an InAs quantum dot in an InAs/InP nanowire, using the tip as a movable gate. Images of dot conductance vs. tip position at T = 4.2 K show concentric rings as electrons are added, starting with the first electron. The SPM can locate a dot along a nanowire and individually tune its charge, abilities that will be very useful for the control of coupled nanowire dots

Observation of metastable Aβ amyloid protofibrils by atomic force microscopy

AbstractBackground: Brain amyloid plaque, a diagnostic feature of Alzheimer's disease (AD), contains an insoluble fibrillar core that is composed primarily of variants of the β-amyloid protein (Aβ). As Aβ amyloid fibrils may initiate neurodegeneration, the inhibition of fibril formation is a possible therapeutic strategy. Very little is known about the early steps of the process, however.Results: Atomic force microscopy was used to follow amyloid fibril formation in vitro by the Aβ variants Aβ1-40 and Aβ1-42. Both variants first form small ordered aggregates that grow slowly and then rapidly disappear, while prototypical amyloid fibrils of two discrete morphologies appear. Aβ1-42 aggregates much more rapidly than Aβ1-40, which is consistent with its connection to early-onset AD. We propose that the metastable intermediate species be called Aβ amyloid protofibrils.Conclusions: Aβ protofibrils are likely to be intermediates in the in vitro assembly of Aβ amyloid fibrils, but their in vivo role has yet to be determined. Numerous reports of a nonfibrillar form of Aβ aggregate in the brains of individuals who are predisposed to AD suggest the existence of a precursor form, possibly the protofibril. Thus, stabilization of Aβ protofibrils may be a useful therapeutic strategy

Self-directed growth of AlGaAs core-shell nanowires for visible light applications

Al(0.37)Ga(0.63)As nanowires (NWs) were grown in a molecular beam epitaxy system on GaAs(111)B substrates. Micro-photoluminescence measurements and energy dispersive X-ray spectroscopy indicated a core-shell structure and Al composition gradient along the NW axis, producing a potential minimum for carrier confinement. The core-shell structure formed during the growth as a consequence of the different Al and Ga adatom diffusion lengths.Comment: 20 pages, 7 figure

Structural biology with carbon nanotube AFM probes

Carbon nanotubes represent ideal probes for high-resolution structural and chemical imaging of biomolecules with atomic force microscopy. Recent advances in fabrication of carbon nanotube probes with sub-nanometer radii promise to yield unique insights into the structure, dynamics and function of biological macromolecules and complexes