Charged residues on the side of the nucleosome contribute to normal Spt16-gene interactions in budding yeast

Previous work in Saccharomyces cerevisiae identified three residues located in close proximity to each other on the side of the nucleosome whose integrity is required for proper association of the Spt16 component of the FACT complex across transcribed genes. In an effort to gain further insights into the parameters that control Spt16 interactions with genes in vivo, we tested the effects of additional histone mutants on Spt16 occupancy across two constitutively transcribed genes. These studies revealed that mutations in several charged residues in the vicinity of the three residues originally identified as important for Spt16-gene interactions also significantly perturb normal association of Spt16 across genes. Based on these and our previous findings, we propose that the charge landscape across the region encompassed by these residues, which we refer to as the Influences Spt16-Gene Interactions or ISGI region, is an important contributor to proper Spt16-gene interactions in vivo.     

The design,synthesis and structure-activity relationships associated with C28 amine-based betulinic acid derivatives as inhibitors of HIV-1 maturation

The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid-substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3, 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC₅₀ values toward the V370A and ΔV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants.     

Correcting for base rates in multidimensional “Who said what?” experiments

The “Who said what?” protocol is a popular experimental paradigm and has been used for 40?years to study spontaneous mental categorization. This paper offers a crucial methodological improvement to calculate unbiased estimates in multidimensional “Who said what?” studies. Previous studies predominantly corrected for base rates by first correcting the base rates and consequently aggregating errors for the two dimensions separately. The paper demonstrates that this procedure's estimates are biased. A large simulation of over 175,000 experiments and the re-analysis of a pivotal study show that this may increase both false-positive and false-negative error rates in treatment effects and might therefore, respectively, strengthen or weaken evidence for past hypotheses. The paper offers a simple remedy: researchers should first aggregate errors for each dimension and then correct for base rates relying on the method known from single-dimensional studies.     

Cross‐talk between monocyte invasion and astrocyte proliferation regulates scarring in brain injury

Scar formation after brain injury is still poorly understood. To further elucidate such processes, here, we examine the interplay between astrocyte proliferation taking place predominantly at the vascular interface and monocyte invasion. Using genetic mouse models that decrease or increase reactive astrocyte proliferation, we demonstrate inverse effects on monocyte numbers in the injury site. Conversely, reducing monocyte invasion using CCR2^?/? mice causes a strong increase in astrocyte proliferation, demonstrating an intriguing negative cross‐regulation between these cell types at the vascular interface. CCR2^?/? mice show reduced scar formation with less extracellular matrix deposition, smaller lesion site and increased neuronal coverage. Surprisingly, the GFAP⁺ scar area in these mice is also significantly decreased despite increased astrocyte proliferation. Proteomic analysis at the peak of increased astrocyte proliferation reveals a decrease in extracellular matrix synthesizing enzymes in the injury sites of CCR2^?/? mice, highlighting how early key aspects of scar formation are initiated. Taken together, we provide novel insights into the cross‐regulation of juxtavascular proliferating astrocytes and invading monocytes as a crucial mechanism of scar formation upon brain injury.     

Socioecological Factors Affecting Range Defensibility Among Howler Monkeys

Range defensibility is defined as the ability of animals to efficiently move over an area to monitor and defend it. Therefore, range defensibility can help us understand the spatial structure of animal territoriality. We used howler monkeys (Alouatta spp.), a genus for which no agreement on the extent of their territoriality exists, to investigate the factors mediating range defensibility. We compared the defensibility index (D) across 63 groups of howler monkeys, representing 8 different species, based on a literature review. All species, except Alouatta palliata, were classified as potentially territorial according to D, although there was high variability within and among species. Group size had a positive effect on D, probably owing to the greater ability of groups to defend a territory as they become larger. Study area had a negative effect on D, perhaps suggesting that unlike small areas, large areas allow groups to have territories that do not require significant defense from neighbors. However, population density was the factor with the strongest effect on D, with greater monitoring of home ranges under high levels of competition. Our results suggest that howler monkeys are theoretically capable of maintaining a territory and suggest that animals can show a gradient in territoriality, which can be mediated by the competitive context in which it occurs.     

Gonadal steroid preservation of central synaptic input to hamster facial motoneurons following peripheral axotomy

In recent work, we have demonstrated that testosterone propionate accelerates recovery from facial nerve injury in the adult male hamster. Central synaptic stripping following peripheral motor neuron damage is a well-established component of the injury response. Gonadal steroids regulate synaptogenesis in the normal nervous system. In this study, we tested the hypothesis that testosterone propionate administration at the time of facial nerve transection alters the synaptic connectivity of injured facial motoneurons. Adult hamsters were subjected to right facial nerve transection at the level of the stylomastoid foramen. Half the animals received subcutaneous implants of testosterone propionate; the other half were sham implanted. At 5 days postoperative, the animals were killed by intracardiac perfusion-fixation, and the control and axotomized facial nuclear groups from the brainstems of nonhormone- and testosterone propionate-treated animals processed for routine transmission electron microscopy. Quantiative analysis of the synaptic ratio (percent somal membrane covered by synaptic profiles) and the average length of axosomatic synapses was accomplished. The results indicate that axotomy alone resulted in an 81% reduction in the synaptic ratio and a 26% decrease in the average synaptic length of axosomatic synapses. Exposure to testosterone propionate from the time of facial nerve transection resulted in only a 48% reduction in the synaptic ratio and a 16% decrease in the average synaptic length of axosomatic synapses following injury. Thus, testosterone propionate significantly attenuated the amount of synaptic stripping that occurred at 5 days postoperative and the decrease in average length of the remaining synapses as well. It is concluded that gonadal steroids modulate central synaptic plasticity following peripheral nerve injury. The results are discussed in light of our recent findings of steroidal effects on the central astrocyctic response to facial nerve injury as well.     

Cloning and characterization of the mammalian-specific nicolin 1 gene (NICN1) encoding a nuclear 24 kDa protein.

We have identified a novel mammalian gene, termed nicolin 1 gene (NICN1), that is present in human, dog and mouse, whereas it is absent from the available genome sequences of nonmammalian organisms. The NICN1 gene consists of six exons and spans about 6 kb of genomic DNA. It encodes a 213 amino acid protein that does not belong to any known protein family. Experiments using green fluorescent protein (GFP)-tagged nicolin 1 fusion proteins indicate that nicolin 1 is a nuclear protein. Northern analysis and semiquantitative RT-PCR demonstrated that the 2.5 kb NICN1 mRNA is expressed in a tissue-specific manner. The highest NICN1 expression levels are found in brain, testis, liver, and kidney. On the other hand the NICN1 expression is weak in spleen, leukocytes, small intestine and colon. The NICN1 gene is also expressed during development.