Genetic Diversity of Four Filipino Negrito Populations from Luzon: Comparison of Male and Female Effective Population Sizes and Differential Integration of Immigrants into Aeta and Agta Communities

Genetic data corresponding to four negrito populations (two Aeta and two Agta; n = 120) from the Luzon region of the Philippines have been analyzed. These data comprise mitochondrial DNA (mtDNA) hypervariable segment 1 haplotypes and haplogroups, Y-chromosome haplogroups and short tandem repeats (STRs), autosomal STRs, and X-chromosome STRs. The genetic diversity and structure of the populations were investigated at a local, regional, and interregional level. We found a high level of autosomal differentiation, combined with no significant reduction in diversity, consistent with long-term settlement of the Luzon region by the ancestors of the Agta and Aeta followed by reduced gene flow between these two ethnolinguistic groups. Collectively, the Aeta have a much higher ratio of female:male effective population size than do the Agta, a finding that supports phylogenetic analysis of their mtDNA and Y-chromosome haplogroups, which suggests different genetic sex-biased contributions from putative Austronesian source populations. We propose that factors of social organization that led to the reduction in Agta female effective population size may also be linked to the limited incorporation of female lineages associated with the settlement of the Philippines by Austronesian speakers; conversely, the reduction in Aeta male effective population size, relative to females, could be indicative of a limited incorporation of male lineages associated with this demographic process

A matrix solution to pentagon equation with anticommuting variables

We construct a solution to pentagon equation with anticommuting variables living on two-dimensional faces of tetrahedra. In this solution, matrix coordinates are ascribed to tetrahedron vertices. As matrix multiplication is noncommutative, this provides a "more quantum" topological field theory than in our previous works

State Sum Models and Simplicial Cohomology

We study a class of subdivision invariant lattice models based on the gauge group $Z_{p}$, with particular emphasis on the four dimensional example. This model is based upon the assignment of field variables to both the $1$- and $2$-dimensional simplices of the simplicial complex. The property of subdivision invariance is achieved when the coupling parameter is quantized and the field configurations are restricted to satisfy a type of mod-$p$ flatness condition. By explicit computation of the partition function for the manifold $RP^{3} \times S^{1}$, we establish that the theory has a quantum Hilbert space which differs from the classical one.Comment: 28 pages, Latex, ITFA-94-13, (Expanded version with two new sections

The influence of the cosmological expansion on local systems

Following renewed interest, the problem of whether the cosmological expansion affects the dynamics of local systems is reconsidered. The cosmological correction to the equations of motion in the locally inertial Fermi normal frame (the relevant frame for astronomical observations) is computed. The evolution equations for the cosmological perturbation of the two--body problem are solved in this frame. The effect on the orbit is insignificant as are the effects on the galactic and galactic--cluster scales.Comment: To appear in the Astrophysical Journal, Late

Quantum geometry with intrinsic local causality

The space of states and operators for a large class of background independent theories of quantum spacetime dynamics is defined. The SU(2) spin networks of quantum general relativity are replaced by labelled compact two-dimensional surfaces. The space of states of the theory is the direct sum of the spaces of invariant tensors of a quantum group G_q over all compact (finite genus) oriented 2-surfaces. The dynamics is background independent and locally causal. The dynamics constructs histories with discrete features of spacetime geometry such as causal structure and multifingered time. For SU(2) the theory satisfies the Bekenstein bound and the holographic hypothesis is recast in this formalism.Comment: Latex 33 pages, 7 Figure, epsfi

Search for Specific Biomarkers of IFNβ Bioactivity in Patients with Multiple Sclerosis

Myxovirus A (MxA), a protein encoded by the MX1 gene with antiviral activity, has proven to be a sensitive measure of IFNβ bioactivity in multiple sclerosis (MS). However, the use of MxA as a biomarker of IFNβ bioactivity has been criticized for the lack of evidence of its role on disease pathogenesis and the clinical response to IFNβ. Here, we aimed to identify specific biomarkers of IFNβ bioactivity in order to compare their gene expression induction by type I IFNs with the MxA, and to investigate their potential role in MS pathogenesis. Gene expression microarrays were performed in PBMC from MS patients who developed neutralizing antibodies (NAB) to IFNβ at 12 and/or 24 months of treatment and patients who remained NAB negative. Nine genes followed patterns in gene expression over time similar to the MX1, which was considered the gold standard gene, and were selected for further experiments: IFI6, IFI27, IFI44L, IFIT1, HERC5, LY6E, RSAD2, SIGLEC1, and USP18. In vitro experiments in PBMC from healthy controls revealed specific induction of selected biomarkers by IFNβ but not IFNγ, and several markers, in particular USP18 and HERC5, were shown to be significantly induced at lower IFNβ concentrations and more selective than the MX1 as biomarkers of IFNβ bioactivity. In addition, USP18 expression was deficient in MS patients compared with healthy controls (p = 0.0004). We propose specific biomarkers that may be considered in addition to the MxA to evaluate IFNβ bioactivity, and to further explore their implication in MS pathogenesis

Neutralizing antibodies explain the poor clinical response to Interferon beta in a small proportion of patients with Multiple Sclerosis: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Neutralizing antibodies (NAbs) against Interferon beta (IFNβ) are reported to be associated with poor clinical response to therapy in multiple sclerosis (MS) patients. We aimed to quantify the contribution of NAbs to the sub-optimal response of IFNβ treatment.</p> <p>Methods</p> <p>We studied the prevalence of NAbs in MS patients grouped according to their clinical response to IFNβ during the treatment period. Patients were classified as: group A, developing ≥ 1 relapse after the first 6 months of therapy; group B, exhibiting confirmed disability progression after the first 6 months of therapy, with or without superimposed relapses; group C, presenting a stable disease course during therapy. A cytopathic effect assay tested the presence of NAbs in a cohort of ambulatory MS patients treated with one of the available IFNβ formulations for at least one year. NAbs positivity was defined as NAbs titre ≥ 20 TRU.</p> <p>Results</p> <p>Seventeen patients (12.1%) were NAbs positive. NAbs positivity correlated with poorer clinical response (<it>p </it>< 0.04). As expected, the prevalence of NAbs was significantly lower in Group C (2.1%) than in Group A (17.0%) and Group B (17.0%). However, in the groups of patients with a poor clinical response (A, B), NAbs positivity was found only in a small proportion of patients.</p> <p>Conclusion</p> <p>The majority of patients with poor clinical response are NAbs negative suggesting that NAbs explains only partially the sub-optimal response to IFNβ.</p

Discrete approaches to quantum gravity in four dimensions

The construction of a consistent theory of quantum gravity is a problem in theoretical physics that has so far defied all attempts at resolution. One ansatz to try to obtain a non-trivial quantum theory proceeds via a discretization of space-time and the Einstein action. I review here three major areas of research: gauge-theoretic approaches, both in a path-integral and a Hamiltonian formulation, quantum Regge calculus, and the method of dynamical triangulations, confining attention to work that is strictly four-dimensional, strictly discrete, and strictly quantum in nature.Comment: 33 pages, invited contribution to Living Reviews in Relativity; the author welcomes any comments and suggestion

Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism

<p>Abstract</p> <p>Background</p> <p>The metabolism of amyloid precursor protein (APP) and β-amyloid (Aβ) is widely studied in Alzheimer's disease, where Aβ deposition and plaque development are essential components of the pathogenesis. However, the physiological role of amyloid in the adult nervous system remains largely unknown. We have previously found altered cerebral amyloid metabolism in other neuroinflammatory conditions. To further elucidate this, we investigated amyloid metabolism in patients with Lyme neuroborreliosis (LNB).</p> <p>Methods</p> <p>The first part of the study was a cross-sectional cohort study in 61 patients with acute facial palsy (19 with LNB and 42 with idiopathic facial paresis, Bell's palsy) and 22 healthy controls. CSF was analysed for the β-amyloid peptides Aβ38, Aβ40 and Aβ42, and the amyloid precursor protein (APP) isoforms α-sAPP and β-sAPP. CSF total-tau (T-tau), phosphorylated tau (P-tau) and neurofilament protein (NFL) were measured to monitor neural cell damage. The second part of the study was a prospective cohort-study in 26 LNB patients undergoing consecutive lumbar punctures before and after antibiotic treatment to study time-dependent dynamics of the biomarkers.</p> <p>Results</p> <p>In the cross-sectional study, LNB patients had lower levels of CSF α-sAPP, β-sAPP and P-tau, and higher levels of CSF NFL than healthy controls and patients with Bell's palsy. In the prospective study, LNB patients had low levels of CSF α-sAPP, β-sAPP and P-tau at baseline, which all increased towards normal at follow-up.</p> <p>Conclusions</p> <p>Amyloid metabolism is altered in LNB. CSF levels of α-sAPP, β-sAPP and P-tau are decreased in acute infection and increase after treatment. In combination with earlier findings in multiple sclerosis, cerebral SLE and HIV with cerebral engagement, this points to an influence of neuroinflammation on amyloid metabolism.</p