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Phenotypic properties of transmitted founder HIV-1
No full textDefining the virus�host interactions responsible for HIV-1 transmission, including the phenotypic requirements of viruses capable of establishing de novo infections, could be important for AIDS vaccine development. Previous analyses have failed to identify phenotypic properties other than chemokine receptor 5 (CCR5) and CD4+ T-cell tropism that are preferentially associated with viral transmission. However, most of these studies were limited to examining envelope (Env) function in the context of pseudoviruses. Here, we generated infectious molecular clones of transmitted founder (TF; n = 27) and chronic control (CC; n = 14) viruses of subtypes B (n = 18) and C (n = 23) and compared their phenotypic properties in assays specifically designed to probe the earliest stages of HIV-1 infection. We found that TF virions were 1.7-fold more infectious (P = 0.049) and contained 1.9-fold more Env per particle (P = 0.048) compared with CC viruses. TF viruses were also captured by monocyte-derived dendritic cells 1.7-fold more efficiently (P = 0.035) and more readily transferred to CD4+ T cells (P = 0.025). In primary CD4+ T cells, TF and CC viruses replicated with comparable kinetics; however, when propagated in the presence of IFN-α, TF viruses replicated to higher titers than CC viruses. This difference was significant for subtype B (P = 0.000013) but not subtype C (P = 0.53) viruses, possibly reflecting demographic differences of the respective patient cohorts. Together, these data indicate that TF viruses are enriched for higher Env content, enhanced cell-free infectivity, improved dendritic cell interaction, and relative IFN-α resistance. These viral properties, which likely act in concert, should be considered in the development and testing of AIDS vaccines
Antigenicity and Immunogenicity of Transmitted/Founder, Consensus, and Chronic Envelope Glycoproteins of Human Immunodeficiency Virus Type 1
No full textHuman immunodeficiency virus type 1 (HIV-1) vaccine development requires selection of appropriate envelope (Env) immunogens. Twenty HIV-1 Env glycoproteins were examined for their ability to bind human anti-HIV-1 monoclonal antibodies (MAbs) and then used as immunogens in guinea pigs to identify promising immunogens. These included five Envs derived from chronically infected individuals, each representing one of five common clades and eight consensus Envs based on these five clades, as well as the consensus of the entire HIV-1 M group, and seven transmitted/founder (T/F) Envs from clades B and C. Sera from immunized guinea pigs were tested for neutralizing activity using 36 HIV-1 Env-pseudotyped viruses. All Envs bound to CD4 binding site, membrane-proximal, and V1/V2 MAbs with similar apparent affinities, although the T/F Envs bound with higher affinity to the MAb 17b, a CCR5 coreceptor binding site antibody. However, the various Envs differed in their ability to induce neutralizing antibodies. Consensus Envs elicited the most potent responses, but neutralized only a subset of viruses, including mostly easy-to-neutralize tier 1 and some more-difficult-to-neutralize tier 2 viruses. T/F Envs elicited fewer potent neutralizing antibodies but exhibited greater breadth than chronic or consensus Envs. Finally, chronic Envs elicited the lowest level and most limited breadth of neutralizing antibodies overall. Thus, each group of Env immunogens elicited a different antibody response profile. The complementary benefits of consensus and T/F Env immunogens raise the possibility that vaccines utilizing a combination of consensus and T/F Envs may be able to induce neutralizing responses with greater breadth and potency than single Env immunogens
The local Langlands correspondence for inner forms of SL_n
No full textLet be a non-archimedean local field. We establish the local Langlands correspondence for all inner forms of the group . It takes the form of a bijection between, on the one hand, conjugacy classes of Langlands parameters for enhanced with an irreducible representation of an S-group and, on the other hand, the union of the spaces of irreducible admissible representations of all inner forms of . An analogous result is shown in the archimedean case.
To settle the case where has positive characteristic, we employ the method of close fields. We prove that this method is compatible with the local Langlands correspondence for inner forms of , when the fields are close enough compared to the depth of the representations
The Matrix Unwinding Function, with an Application to Computing the Matrix Exponential
No full textA new matrix function corresponding to the scalar unwinding number of
Corless, Hare, and Jeffrey is introduced.
This matrix unwinding function, , is shown to
be a valuable tool for deriving
identities involving the matrix logarithm and
fractional matrix powers,
revealing, for example, the
precise relation between and .
The unwinding function is also shown to be closely connected with the matrix
sign function.
An algorithm for computing the unwinding function based on the
Schur--Parlett method with a special reordering is proposed.
It is shown that matrix argument reduction using the function
,
which has eigenvalues with imaginary parts in the interval
and for which \e^A = \e^{\mathrm{mod}(A)},
can give significant computational savings in the evaluation
of the exponential by scaling and squaring algorithms
Estimating the Condition Number of the Frechet Derivative of a Matrix Function
No full textThe Fr\'{e}chet derivative of a matrix function
is used in a variety of applications
and several algorithms are available for computing it.
We define a condition number for the Fr\'{e}chet derivative
and derive upper and lower bounds for it that differ by at most a factor
.
For a wide class of functions
we derive an algorithm for estimating the 1-norm condition number that
requires flops given
flops algorithms for evaluating and ;
in practice it produces estimates correct to within a factor .
Numerical experiments show the new algorithm to be much more
reliable than a previous heuristic estimate of conditioning
A model of yeast glycolysis based on a consistent kinetic characterisation of all its enzymes
Get PDFWe present an experimental and computational pipeline for the generation of kinetic models of metabolism, and demonstrate its application to glycolysis in Saccharomyces cerevisiae. Starting from an approximate mathematical model, we employ a �cycle of knowledge� strategy, identifying the steps with most control over flux. Kinetic parameters of the individual isoenzymes within these steps are measured experimentally under a standardised set of conditions. Experimental strategies are applied to establish a set of in vivo concentrations for isoenzymes and metabolites. The data are integrated into a mathematical model that is used to predict a new set of metabolite concentrations and reevaluate the control properties of the system. This bottom-up modelling study reveals that control over the metabolic network most directly involved in yeast glycolysis is more widely distributed than previously thought
Implementation and Analysis of Katsevich Reconstruction for Helical Scan CT
Get PDFIn performing X-ray Computed Tomography two major constraints are the required acquisition time and X-ray dose for the scans. One method of reducing these is to take the scan by moving source and detector in one continuous helix relative to the object, rather than taking several separate circular scans. This Dissertation examines two implementations of the derivatives required for the Katsevich reconstruction algorithm for helical cone beam micro-CT, both the original implementation suggested by Noo et al.[2003] and an alternate formulation proposed by Katsevich[2011]. A new bound on a parameter used by the second formulation is suggested and methods for dealing with practical difficulties when reconstructing real scan data are proposed
Counterexamples to a rank analogue of the Shepherd--Leedham-Green--McKay theorem on finite -groups of maximal class
Get PDFBy the Shepherd--Leedham-Green--McKay theorem on finite -groups of maximal class, if a finite -group of order has nilpotency class , then it has a subgroup of
nilpotency class at most with index bounded in terms of . Counterexamples to a rank analogue of this theorem are
constructed, which give a negative solution to Problem~16.103 in Kourovka Notebook. Moreover, it is shown that there are no functions and such that any -generator finite -group all of whose factors of the lower central series, starting from the second, are cyclic
would necessarily have a normal subgroup of derived length at most with quotient of rank at most . The required examples of finite -groups are constructed as quotients of torsion-free nilpotent groups, which are abstract -generator subgroups of nilpotent divisible torsion-free groups that are in the Mal'cev correspondence with ``truncated'' Witt algebras
Rank and order of a finite group admitting a Frobenius group of automorphisms
Get PDFSuppose that a finite group admits a Frobenius group of automorphisms of coprime order
with kernel and complement . In the case where is a finite -group such that it is proved
that the order of is bounded above in terms of the order of and the order of the fixed-point subgroup
of the complement, and the rank of is bounded above in terms of and the rank of
. Earlier such results were known under the stronger assumption that the kernel acts on
fixed-point-freely. As a corollary, in the case where is an arbitrary finite group with a Frobenius group of
automorphisms of coprime order with kernel and complement , estimates are obtained of the form
for the order, and
for the rank, where
and are some functions of two variables
L-packets and formal degrees for SL_2(K) with K a local function field of characteristic 2
Get PDFLet G = SL_2(K) with K a local function field of characteristic 2. We review Artin-Schreier theory for the field K, and show that this leads to a parametrization of L-packets in the smooth dual of G. We relate this to a recent geometric conjecture. The L-packets in the principal series are parametrized by quadratic extensions, and the supercuspidal L-packets by biquadratic extensions. We compute the formal degrees of the elements in the supercuspidal packets