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1.  Cryptic Genetic Variation Can Make “Irreducible Complexity” a Common Mode of Adaptation in Sexual Populations 
The existence of complex (multiple-step) genetic adaptations that are ‘irreducible’ (i.e., all partial combinations are less fit than the original genotype) is one of the longest standing problems in evolutionary biology. In standard genetics parlance, these adaptations require the crossing of a wide adaptive valley of deleterious intermediate stages. Here we demonstrate, using a simple model, that evolution can cross wide valleys to produce ‘irreducibly complex’ adaptations by making use of previously cryptic mutations. When revealed by an evolutionary capacitor, previously cryptic mutants have higher initial frequencies than do new mutations, bringing them closer to a valley-crossing saddle in allele frequency space. Moreover, simple combinatorics imply an enormous number of candidate combinations exist within available cryptic genetic variation. We model the dynamics of crossing of a wide adaptive valley after a capacitance event using both numerical simulations and analytical approximations. Although individual valley crossing events become less likely as valleys widen, by taking the combinatorics of genotype space into account, we see that revealing cryptic variation can cause the frequent evolution of complex adaptations.
PMCID: PMC4258170  PMID: 25178652
Complex adaptation; adaptive valley; evolutionary capacitance; theoretical population genetics; Moran model
2.  Risk Factors for Mortality among MDR- and XDR-TB Patients in a High HIV-Prevalence Setting 
Recent studies suggest that the prevalence of drug-resistant TB in sub-Saharan Africa may be rising. This is of concern since HIV co-infection in MDR- and XDR-TB has been associated with exceedingly rates of mortality.
To identify risk factors associated with mortality in MDR- and XDR-TB patients co-infected with HIV in South Africa.
Case-control study of patients who died of all causes within two years of diagnosis with MDR- or XDR-TB.
Among 123 MDR-TB patients, 78 (63%) died following diagnosis. CD4 count less than 50 (HR 4.64, p=0.01) and 51-200 cells/mm3 (HR 4.17, p=0.008) were the strongest independent risk factors for mortality. Among 139 XDR-TB patients, 111 (80%) died. CD4 count less than 50 cells/mm3 (HR 4.46, p=0.01) and resistance to all six drugs tested (HR 2.54, p=0.04) were the principal risk factors. Use of antiretroviral therapy (ART) was protective (HR 0.34, p=0.009).
Mortality in MDR- and XDR-TB was associated with greater degree of immunosuppression and drug resistance. Efforts to reduce mortality must focus on preventing the amplification of resistance by strengthening TB treatment programs, as well as, reducing the pool of immunosuppressed HIV-infected patients through aggressive HIV testing and ART initiation.
PMCID: PMC3302205  PMID: 22236852
multidrug-resistant tuberculosis; extensively drug-resistant tuberculosis; risk factors; mortality; HIV/TB Co-infection
3.  Antiviral Activities in Human Saliva 
Advances in Dental Research  2011;23(1):34-37.
In this review, the authors survey the large number of antibacterial and antiviral proteins present in human saliva. Of interest, most of these antibacterial proteins display antiviral activity, typically against specific viral pathogens. The review focuses on one protein that interacts with both bacteria and viruses—gp340, originally referred to as salivary agglutinin. In the oral cavity, soluble gp340 binds to and aggregates a variety of bacteria, and this is thought to increase bacterial clearance from the mouth. However, when bound to the tooth surface, gp340 promotes bacterial adherence. In the oral cavity, most gp340 is found soluble in saliva and can function as a specific inhibitor of infectivity of HIV-1 and influenza A. In contrast, in the female reproductive track, most gp340 is bound to the cell surface, where it can promote HIV-1 infection.
PMCID: PMC3144043  PMID: 21441478
HIV; AIDS; viral; antiviral; innate immune system
4.  Variations of response time in a selective attention task are linked to variations of functional connectivity in the attentional network 
NeuroImage  2010;54(1):541-549.
Although variations of response time (RT) within a particular experimental condition are typically ignored, they may sometimes reflect meaningful changes in the efficiency of cognitive and neural processes. In the present study, we investigated whether trial-by-trial variations of response time (RT) in a cross-modal selective attention task were associated with variations of functional connectivity between brain regions that are thought to underlie attention. Sixteen healthy young adults performed an audiovisual selective attention task, which involved attending to a relevant visual letter while ignoring an irrelevant auditory letter, as we recorded their brain activity using functional magnetic resonance imaging (fMRI). In line with predictions, variations of RT were associated with variations of functional connectivity between the anterior cingulate cortex and various other brain regions that are posited to underlie attentional control, such as the right dorsolateral prefrontal cortex and bilateral regions of the posterior parietal cortex. They were also linked to variations of functional connectivity between anatomically early and anatomically late regions of the relevant-modality visual cortex whose communication is thought to be modulated by attentional control processes. By revealing that variations of RT in a selective attention task are linked to variations of functional connectivity in the attentional network, the present findings suggest that variations of attention may contribute to trial-by-trial fluctuations of behavioral performance.
PMCID: PMC2962675  PMID: 20728549
attention; visual; auditory; functional connectivity; fMRI; response time
5.  The neural circuitry underlying the executive control of auditory spatial attention 
Brain research  2007;1134(1):187-198.
Although a fronto-parietal network has consistently been implicated in the control of visual spatial attention, the network that guides spatial attention in the auditory domain is not yet clearly understood. To investigate this issue, we measured brain activity using functional magnetic resonance imaging while participants performed a cued auditory spatial attention task. We found that cued orienting of auditory spatial attention activated a medial-superior distributed fronto-parietal network, as well as auditory regions of the sensory cortex. In addition, we found cue-triggered increases of activity in the auditory sensory cortex prior to the occurrence of an auditory target, suggesting that auditory attentional control operates in part by biasing processing in sensory cortex in favor of expected target stimuli. Finally, an exploratory cross-study comparison further indicated several common frontal and parietal regions as being involved in the control of both visual and auditory spatial attention. Thus, the present findings not only reveal the network of brain areas underlying endogenous spatial orienting in the auditory modality, but also suggest that the control of spatial attention in different sensory modalities is enabled in part by some common, supramodal neural mechanisms.
PMCID: PMC3130498  PMID: 17204249
fMRI; supramodal; top-down control; fronto-parietal network
6.  Momentary reductions of attention permit greater processing of irrelevant stimuli 
NeuroImage  2009;48(3):609-615.
Momentary reductions of attention can have extremely adverse outcomes, but it remains unclear whether increased distraction from irrelevant stimuli contributes to such outcomes. To investigate this hypothesis, we examined trial-by-trial relationships between brain activity and response time in twenty healthy adults while they performed a cross-modal selective attention task. In each trial, participants identified a relevant visual letter while ignoring an irrelevant auditory letter, which was mapped either to the same response as the visual letter (congruent trials) or to a different response (incongruent trials). As predicted, reductions of attention (i.e., increases of response time) were associated not only with decreased activity in sensory regions that processed the relevant visual stimuli, suggesting a failure to enhance the processing of those stimuli, but also with increased activity in sensory regions that processed the irrelevant auditory stimuli, suggesting a failure to suppress the processing of those stimuli. Reductions of attention were also linked to larger increases of activity in incongruent than in congruent trials in anterior cingulate regions that detect response conflict, suggesting that failing to suppress the sensory processing of the irrelevant auditory stimuli during attentional reductions allowed those stimuli to more readily activate conflicting responses in incongruent trials. These findings indicate that heightened levels of distraction during momentary reductions of attention likely stem, at least in part, from increased processing of irrelevant stimuli.
PMCID: PMC2738758  PMID: 19596451
attention; auditory; visual; response conflict; fMRI; cognitive
7.  fMRI evidence for both generalized and specialized components of attentional control 
Brain research  2007;1177:90-102.
A central question in the study of selective attention is whether top-down attentional control mechanisms are generalized or specialized for the type of information that is to be attended. The current study examined this question using a voluntary orienting task that cued observers to attend to either one of two locations or to one of two colors. Location (spatial) and color (nonspatial) conditions were presented either randomly intermixed within the same block of trials or in separate blocks. Functional magnetic resonance imaging revealed that directing attention to a location or to a color activated a network of overlapping dorsal frontal and parietal areas, previously implicated in attentional control. The pattern of observed overlap was not affected by the intermixed versus blocked presentation of location and color conditions. Although portions of the frontal-parietal network were more active in response to location cues than to color cues, a secondary analysis also revealed that medial dorsal frontal and parietal cortex were specifically engaged in shifting visual attention regardless of the cued dimension (location or color). Together, the present results support the conclusion that attentional control is the combination of a generalized network that works in concert with sub-regions of the fronto-parietal network that are highly specialized for directing attention based on the content of the to-be-attended information.
PMCID: PMC2710450  PMID: 17916338
attentional control; fMRI; selective attention; spatial attention; nonspatial attention; frontoparietal network
8.  Cognitive control in social situations: A role for the dorsolateral prefrontal cortex 
NeuroImage  2007;40(2):955-962.
Using functional magnetic resonance imaging (fMRI), we investigated brain activity elicited by a computer-animated child’s actions that appeared consistent and inconsistent with a computer-animated adult’s instuctions. Participants observed a computer-animated adult verbally instructing a computer-animated child to touch one of two objects. The child performed correctly in half the trials and incorrectly in the other half. We observed significantly greater activity when the child performed incorrectly compared to correctly in regions of the dorsolateral prefrontal cortex (DLPFC) that have been implicated in maintaining our intentions in working memory and implementing cognitive control. However, no such effects were found in regions of the posterior superior temporal sulcus (posterior STS) that have been posited to interpret other people’s behavior. These findings extend the role of the DLPFC in cognitive control to evaluating the social outcomes of other people’s behavior and provide important new constraints for theories of how the posterior STS contributes to social cognition.
PMCID: PMC2522237  PMID: 18234518
fMRI; social cognition; dorsolateral prefrontal cortex; superior temporal sulcus; mirror neuron
9.  Role of dendritic cells in immunopathogenesis of human immunodeficiency virus infection. 
Clinical Microbiology Reviews  1997;10(2):358-367.
The role of dendritic cells (DC) in the pathogenesis of human immunodeficiency virus (HIV) disease has been a subject of considerable interest for several years. Initial studies focused on the infection, dysfunction, and depletion of DC in HIV-infected individuals. More recent studies have begun to identify the functional role of DC in the initiation and propagation of viral replication in T cells in HIV-infected individuals. This review discusses recent data regarding the role of DC in HIV disease with the aim of delineating basic immunopathogenic principles of infection and the development of therapeutic strategies.
PMCID: PMC172924  PMID: 9105759
10.  Inherited resistance to HIV-1 conferred by an inactivating mutation in CC chemokine receptor 5: studies in populations with contrasting clinical phenotypes, defined racial background, and quantified risk. 
Molecular Medicine  1997;3(1):23-36.
BACKGROUND: CC chemokine receptor 5 (CCR5) is a cell entry cofactor for macrophage-tropic isolates of human immunodeficiency virus-1 (HIV-1). Recently, an inactive CCR5 allele (designated here as CCR5-2) was identified that confers resistance to HIV-1 infection in homozygotes and slows the rate of progression to AIDS in heterozygotes. The reports conflict on the effect of heterozygous CCR5-2 on HIV-1 susceptibility, and race and risk levels have not yet been fully analyzed. Here we report our independent identification of CCR5-2 and test its effects on HIV-1 pathogenesis in individuals with contrasting clinical outcomes, defined race, and quantified risk. MATERIALS AND METHODS: Mutant CCR5 alleles were sought by directed heteroduplex analysis of genomic DNA from random blood donors. Genotypic frequencies were then determined in (1) random blood donors from North America, Asia, and Africa; (2) HIV-1+ individuals; and (3) highly exposed-seronegative homosexuals with quantified risk. RESULTS: CCR5-2 was the only mutant allele found. It was common in Caucasians, less common in other North American racial groups, and not detected in West Africans or Tamil Indians. Homozygous CCR5-2 frequencies differed reciprocally in highly exposed-seronegative (4.5%, n = 111) and HIV-1-seropositive (0%, n = 614) Caucasians relative to Caucasian random blood donors (0.8%, n = 387). This difference was highly significant (p < 0.0001). By contrast, heterozygous CCR5-2 frequencies did not differ significantly in the same three groups (21.6, 22.6, and 21.7%, respectively). A 55% increase in the frequency of heterozygous CCR5-2 was observed in both of two cohorts of Caucasian homosexual male, long-term nonprogressors compared with other HIV-1+ Caucasian homosexuals (p = 0.006) and compared with Caucasian random blood donors. Moreover, Kaplan-Meier estimates indicated that CCR5-2 heterozygous seroconvertors had a 52.6% lower risk of developing AIDS than homozygous wild-type seroconvertors. CONCLUSIONS: The data suggest that homozygous CCR5-2 is an HIV-1 resistance factor in Caucasians with complete penetrance, and that heterozygous CCR5-2 slows the rate of disease progression in infected Caucasian homosexuals. Since the majority (approximately 96%) of highly exposed-seronegative individuals tested are not homozygous for CCR5-2, other resistance factors must exist. Since CCR5-2 homozygotes have no obvious clinical problems, CCR5 may be a good target for the development of novel antiretroviral therapy.
PMCID: PMC2230106  PMID: 9132277

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