CXCL10 is the key ligand for CXCR3 on CD8+ effector T cells involved in immune surveillance of the lymphocytic choriomeningitis virus-infected central nervous system

IFN-gamma-inducible protein 10/CXCL10 is a chemokine associated with type 1 T cell responses, regulating the migration of activated T cells through binding to the CXCR3 receptor. Expression of both CXCL10 and CXCR3 are observed during immunopathological diseases of the CNS, and this receptor/ligand pair is thought to play a central role in regulating T cell-mediated inflammation in this organ site. In this report, we investigated the role of CXCL10 in regulating CD8(+) T cell-mediated inflammation in the virus-infected brain. This was done through analysis of CXCL10-deficient mice infected intracerebrally with lymphocytic choriomeningitis virus, which in normal immunocompetent mice induces a fatal CD8(+) T cell-mediated meningoencephalitis. We found that a normal antiviral CD8(+) T cell response was generated in CXCL10-deficient mice, and that lack of CXCL10 had no influence on the accumulation of mononuclear cells in the cerebrospinal fluid. However, analysis of the susceptibility of CXCL10-deficient mice to lymphocytic choriomeningitis virus-induced meningitis revealed that these mice just like CXCR3-deficient mice were partially resistant to this disease, whereas wild-type mice invariably died. Furthermore, despite marked up-regulation of the two remaining CXCR3 ligands: CXCL9 and 11, we found a reduced accumulation of CD8(+) T cells in the brain parenchyma around the time point when wild-type mice succumb as a result of CD8(+) T cell-mediated inflammation. Thus, taken together these results indicate a central role for CXCL10 in regulating the accumulation of effector T cells at sites of CNS inflammation, with no apparent compensatory effect of other CXCR3 ligands.     

Distinct action of the retinoblastoma pathway on the DNA replication machinery defines specific roles for cyclin-dependent kinase complexes in prereplication complex assembly and S-phase progression

The retinoblastoma (RB) and p16ink4a tumor suppressors are believed to function in a linear pathway that is functionally inactivated in a large fraction of human cancers. Recent studies have shown that RB plays a critical role in regulating S phase as a means for suppressing aberrant proliferation and controlling genome stability. Here, we demonstrate a novel role for p16ink4a in replication control that is distinct from that of RB. Specifically, p16ink4a disrupts prereplication complex assembly by inhibiting mini-chromosome maintenance (MCM) protein loading in G1, while RB was found to disrupt replication in S phase through attenuation of PCNA function. This influence of p16ink4a on the prereplication complex was dependent on the presence of RB and the downregulation of cyclin-dependent kinase (CDK) activity. Strikingly, the inhibition of CDK2 activity was not sufficient to prevent the loading of MCM proteins onto chromatin, which supports a model wherein the composite action of multiple G1 CDK complexes regulates prereplication complex assembly. Additionally, p16ink4a attenuated the levels of the assembly factors Cdt1 and Cdc6. The enforced expression of these two licensing factors was sufficient to restore the assembly of the prereplication complex yet failed to promote S-phase progression due to the continued absence of PCNA function. Combined, these data reveal that RB and p16ink4a function through distinct pathways to inhibit the replication machinery and provide evidence that stepwise regulation of CDK activity interfaces with the replication machinery at two discrete execution points.     

Is it possible to develop pan-arthropod vaccines?

Hematophagous arthropods that transmit the etiological agents of arthropod-borne diseases have become the focus of anti-vector vaccines, targeted mainly at components of their saliva and midgut. These efforts have been directed mostly towards developing species-specific vaccines. An alternative is to target cross-reactive epitopes that have been preserved during evolution of the arthropods. The N- and O-linked glycans that are attached to arthropod glycoproteins are one of the potential targets of this pan-arthropod vaccine approach. Here, we discuss how genetically modified Drosophila melanogaster cells can be used to synthesize and to deliver these arthropod glycans to vertebrate hosts.     

Contrasting management paradigms for pronghorn in the arid Southwest and their northern range: a review

Pronghorn (Antilocapra americana), a symbol of western North America, experienced diverging population trajectories since the mid-twentieth century, with northern populations showing signs of recovery while those in the arid Southwest have struggled to persist. We conducted a systematic literature review of papers published through August 2023 to understand 3 questions. What are the habitat conditions needed for pronghorn to persist? What management actions can be taken to foster higher quality habitat? Do these actions differ for populations in the arid Southwest compared to their northern counterparts? Although the fundamental habitat requirements for pronghorn persistence have remained constant since the early 2000s, it has become clear that precipitation is a key factor influencing pronghorn populations in the arid Southwest. The precise mechanisms by which precipitation influences pronghorn population dynamics are not yet clear, whether through the availability of free water, by affecting forage quality, or indirectly via predator-prey dynamics. Although range-wide forage enhancement may be impractical, providing additional free water sources could facilitate greater movement, enabling pronghorn to access more and higher quality forage and areas with lower predation risk. To clarify how pronghorn persisted for thousands of years in this harsh environment, we must gain a better understanding of their historical metapopulation and migratory behaviors in the arid Southwest.     

Cholesterol,GM1, and Autism

Disruption of cholesterol metabolism has been hypothesized to contribute to dementia, possibly due to its role in maintaining membrane fluidity as well as the integrity of lipid rafts. Previously, we reported an apparent inverse relationship between membrane cholesterol levels and those of GM1, another lipid that can be found in rafts. This paper describes the observation that red blood cell (RBC) membranes isolated from blood drawn from children diagnosed with autism have on the average significantly less cholesterol and significantly more GM1 than RBC membranes isolated from blood obtained from control children. While cholesterol in the circulation does not cross the blood brain barrier, a generalized defect in its synthesis could affect its concentration in the central nervous system and that, coupled with a change in ganglioside expression, could contribute to development of the behaviors associated with autism.     

Thieno[3,2-d]pyrimidin-4(3H)-one derivatives as PDK1 inhibitors discovered by fragment-based screening

Ligand efficient fragments binding to PDK1 were identified by an NMR fragment-based screening approach. Computational modeling of the fragments bound to the active site led to the design and synthesis of a series of novel 6,7-disubstituted thienopyrimidin-4-one compounds, with low micromolar inhibitory activity against PDK1 in a biochemical enzyme assay.     

The use of next generation sequencing technology to study the effect of radiation therapy on mitochondrial DNA mutation

The human mitochondrial genome has an exclusively maternal mode of inheritance. Mitochondrial DNA (mtDNA) is particularly vulnerable to environmental insults due in part to an underdeveloped DNA repair system, limited to base excision and homologous recombination repair. Radiation exposure to the ovaries may cause mtDNA mutations in oocytes, which may in turn be transmitted to offspring. We hypothesized that the children of female cancer survivors who received radiation therapy may have an increased rate of mtDNA heteroplasmy mutations, which conceivably could increase their risk of developing cancer and other diseases. We evaluated 44 DNA blood samples from 17 Danish and 1 Finnish families (18 mothers and 26 children). All mothers had been treated for cancer as children and radiation doses to their ovaries were determined based on medical records and computational models. DNA samples were sequenced for the entire mitochondrial genome using the Illumina GAII system. Mother's age at sample collection was positively correlated with mtDNA heteroplasmy mutations. There was evidence of heteroplasmy inheritance in that 9 of the 18 families had at least one child who inherited at least one heteroplasmy site from his or her mother. No significant difference in single nucleotide polymorphisms between mother and offspring, however, was observed. Radiation therapy dose to ovaries also was not significantly associated with the heteroplasmy mutation rate among mothers and children. No evidence was found that radiotherapy for pediatric cancer is associated with the mitochondrial genome mutation rate in female cancer survivors and their children.