Altered longevity‐assurance activity of p53:p44 in the mouse causes memory loss,neurodegeneration and premature death

The longevity‐assurance activity of the tumor suppressor p53 depends on the levels of Δ40p53 (p44), a short and naturally occurring isoform of the p53 gene. As such, increased dosage of p44 in the mouse leads to accelerated aging and short lifespan. Here we show that mice homozygous for a transgene encoding p44 (p44^+/+) display cognitive decline and synaptic impairment early in life. The synaptic deficits are attributed to hyperactivation of insulin‐like growth factor 1 receptor (IGF‐1R) signaling and altered metabolism of the microtubule‐binding protein tau. In fact, they were rescued by either Igf1r or Mapt haploinsufficiency. When expressing a human or a ‘humanized’ form of the amyloid precursor protein (APP), p44^+/+ animals developed a selective degeneration of memory‐forming and ‐retrieving areas of the brain, and died prematurely. Mechanistically, the neurodegeneration was caused by both paraptosis‐ and autophagy‐like cell deaths. These results indicate that altered longevity‐assurance activity of p53:p44 causes memory loss and neurodegeneration by affecting IGF‐1R signaling. Importantly, Igf1r haploinsufficiency was also able to correct the synaptic deficits of APP_695/swe mice, a model of Alzheimer’s disease.     

Treatment with apolipoprotein A-1 mimetic peptide reduces lupus-like manifestations in a murine lupus model of accelerated atherosclerosis

Introduction

The purpose of this study was to evaluate the effects of L-4F, an apolipoprotein A-1 mimetic peptide, alone or with pravastatin, in apoE^-/-Fas^-/-C57BL/6 mice that spontaneously develop immunoglobulin G (IgG) autoantibodies, glomerulonephritis, osteopenia, and atherosclerotic lesions on a normal chow diet.

Methods

Female mice, starting at eight to nine weeks of age, were treated for 27 weeks with 1) pravastatin, 2) L-4F, 3) L-4F plus pravastatin, or 4) vehicle control, followed by disease phenotype assessment.

Results

In preliminary studies, dysfunctional, proinflammatory high-density lipoproteins (piHDL) were decreased six hours after a single L-4F, but not scrambled L-4F, injection in eight- to nine-week old mice. After 35 weeks, L-4F-treated mice, in the absence/presence of pravastatin, had significantly smaller lymph nodes and glomerular tufts (P_{L, LP} < 0.05), lower serum levels of IgG antibodies to double stranded DNA (dsDNA) (P_L < 0.05) and oxidized phospholipids (oxPLs) (P_{L, LP} < 0.005), and elevated total and vertebral bone mineral density (P_{L, LP} < 0.01) compared to vehicle controls. Although all treatment groups presented larger aortic root lesions compared to vehicle controls, enlarged atheromas in combination treatment mice had significantly less infiltrated CD68⁺ macrophages (P_LP < 0.01), significantly increased mean α-actin stained area (P_LP < 0.05), and significantly lower levels of circulating markers for atherosclerosis progression, CCL19 (P_{L, LP} < 0.0005) and VCAM-1 (P_L < 0.0002).

Conclusions

L-4F treatment, alone or with pravastatin, significantly reduced IgG anti-dsDNA and IgG anti-oxPLs, proteinuria, glomerulonephritis, and osteopenia in a murine lupus model of accelerated atherosclerosis. Despite enlarged aortic lesions, increased smooth muscle content, decreased macrophage infiltration, and decreased pro-atherogenic chemokines in L-4F plus pravastatin treated mice suggest protective mechanisms not only on lupus-like disease, but also on potential plaque remodeling in a murine model of systemic lupus erythematosus (SLE) and accelerated atherosclerosis.     

Molecular architecture of the ribosome‐bound Hepatitis C Virus internal ribosomal entry site RNA

Internal ribosomal entry sites (IRESs) are structured cis‐acting RNAs that drive an alternative, cap‐independent translation initiation pathway. They are used by many viruses to hijack the translational machinery of the host cell. IRESs facilitate translation initiation by recruiting and actively manipulating the eukaryotic ribosome using only a subset of canonical initiation factor and IRES transacting factors. Here we present cryo‐EM reconstructions of the ribosome 80S‐ and 40S‐bound Hepatitis C Virus (HCV) IRES. The presence of four subpopulations for the 80S•HCV IRES complex reveals dynamic conformational modes of the complex. At a global resolution of 3.9 Å for the most stable complex, a derived atomic model reveals a complex fold of the IRES RNA and molecular details of its interaction with the ribosome. The comparison of obtained structures explains how a modular architecture facilitates mRNA loading and tRNA binding to the P‐site. This information provides the structural foundation for understanding the mechanism of HCV IRES RNA‐driven translation initiation.     

CSF T-Tau/Aβ42 predicts white matter microstructure in healthy adults at risk for Alzheimer's disease

Cerebrospinal fluid (CSF) biomarkers T-Tau and Aβ(42) are linked with Alzheimer's disease (AD), yet little is known about the relationship between CSF biomarkers and structural brain alteration in healthy adults. In this study we examined the extent to which AD biomarkers measured in CSF predict brain microstructure indexed by diffusion tensor imaging (DTI) and volume indexed by T1-weighted imaging. Forty-three middle-aged adults with parental family history of AD received baseline lumbar puncture and MRI approximately 3.5 years later. Voxel-wise image analysis methods were used to test whether baseline CSF Aβ(42), total tau (T-Tau), phosphorylated tau (P-Tau) and neurofilament light protein predicted brain microstructure as indexed by DTI and gray matter volume indexed by T1-weighted imaging. T-Tau and T-Tau/Aβ(42) were widely correlated with indices of brain microstructure (mean, axial, and radial diffusivity), notably in white matter regions adjacent to gray matter structures affected in the earliest stages of AD. None of the CSF biomarkers were related to gray matter volume. Elevated P-Tau and P-Tau/Aβ(42) levels were associated with lower recognition performance on the Rey Auditory Verbal Learning Test. Overall, the results suggest that CSF biomarkers are related to brain microstructure in healthy adults with elevated risk of developing AD. Furthermore, the results clearly suggest that early pathological changes in AD can be detected with DTI and occur not only in cortex, but also in white matter.     

Specific leaf area variations drive acclimation of <Emphasis Type="Italic">Cistus salvifolius</Emphasis> in different light environments

Cistus salvifolius L. is the most widely spread Cistus species around the Mediterranean basin. It colonizes a wide range of habitats growing from sea level to 1,800 m a.s.l., on silicolous and calcicolous soils, in sun areas as well as in the understory of wooded areas. Nevertheless, this species has been mainly investigated in term of its responsiveness to drought. Our aim was to understand which leaf traits allow C. salvifolius to cope with low-light environments. We questioned if biochemical and physiological leaf trait variations in response to a reduced photosynthetic photon flux density were related to leaf morphological plasticity, expressed by variations of specific leaf area (SLA) and its anatomical components (leaf tissue density and thickness). C. salvifolius shrubs growing along the Latium coast (41°43'N,12°18'E, 14 m a.s.l., Italy) in the open and in the understory of a Pinus pinea forest, were selected and the relationships between anatomical, gas exchange, chlorophyll (Chl) fluorescence, and biochemical parameters with SLA and PPFD variations were tested. The obtained results suggested long-term acclimation of the selected shrubs to contrasting light environments. In high-light conditions, leaf nitrogen and Chl contents per leaf area unit, leaf thickness, and Chl a/b ratio increased, thus maximizing net photosynthesis, while in shade photosynthesis, it was downregulated by a significant reduction in the electron transport rate. Nevertheless, the increased pigment-protein complexes and the decreased Chl a/b in shade drove to an increased light-harvesting capacity (i.e. higher actual quantum efficiency of PSII). Moreover, the measured vitality index highlighted the photosynthetic acclimation of C. salvifolius to contrasting light environments. Overall, our results demonstrated the morphological, anatomical, and physiological acclimation of C. salvifolius to a reduced light environment.     

Short‐term physiological plasticity: Trade‐off between drought and recovery responses in three Mediterranean Cistus species

Short‐term physiological plasticity allows plants to thrive in highly variable environments such as the Mediterranean ecosystems. In such context, plants that maximize physiological performance under favorable conditions, such as Cistus spp., are generally reported to have a great cost in terms of plasticity (i.e., a high short‐term physiological plasticity) due to the severe reduction of physiological performance when stress factors occur. However, Cistus spp. also show a noticeable resilience ability in response to stress factors. We hypothesized that in Cistus species the short‐term physiological response to stress and that to subsequent recovery can show a positive trade‐off to offset the costs of the photosynthetic decline under drought. Gas exchange, chlorophyll fluorescence, and water relations were measured in C. salvifolius, C. monspeliensis, and C. creticus subsp. eriocephalus during an imposed experimental drought and subsequent recovery. Plants were grown outdoor in common garden conditions from seeds of different provenances. The short‐term physiological response to stress and that to recovery were quantified via phenotypic plasticity index (PI_stress and PI_recovery, respectively). A linear regression analysis was used to identify the hypothesized trade‐off PI_stress–PI_recovery. Accordingly, we found a positive trade‐off between PI_stress and PI_recovery, which was consistent across species and provenances. This result contributes in explaining the profit, more than the cost, of a higher physiological plasticity in response to short‐term stress imposition for Cistus spp because the costs of a higher PI_stress are payed back by an as much higher PI_recovery. The absence of leaf shedding during short‐term drought supports this view. The trade‐off well described the relative variations of gas exchange and water relation parameters. Moreover, the results were in accordance with the ecology of this species and provide the first evidence of a consistent trade‐off between the short‐term physiological responses to drought and recovery phases in Mediterranean species.     

Hormone-regulated expression and distribution of versican in mouse uterine tissues

Background  

Remodeling of the extracellular matrix is one of the most striking features observed in the uterus during the estrous cycle and after hormone replacement. Versican (VER) is a hyaluronan-binding proteoglycan that undergoes RNA alternative splicing, generating four distinct isoforms. This study analyzed the synthesis and distribution of VER in mouse uterine tissues during the estrous cycle, in ovariectomized (OVX) animals and after 17beta-estradiol (E2) and medroxyprogesterone (MPA) treatments, either alone or in combination.