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Visual impairment is commonly reported as a consequence of heavy prenatal ethanol exposure in humans. Children generally display characteristic cranio-facial dysmorphology and represent typical severe cases of foetal alcohol syndrome. Binge-like rodent model systems have concluded that third trimester equivalent ethanol exposure results in widespread apoptosis in the visual system from the retina to the visual cortex. Neither clinical nor animal studies address the consequences of more moderate prenatal ethanol exposure on the visual system. The current study uses a naturalistic and voluntary consumption approach in non-human primates (Chlorocebus sabeus) in order to more closely model prenatal ethanol consumption patterns in humans. Pregnant vervet monkeys voluntarily drank on average 2.418 ± 0.296 g etoh/kg/day four times a week during the third trimester. Using unbiased stereology, we estimated the neuronal and glial population of the parvocellular (P) and magnocellular (M) layers of the lateral geniculate nucleus (LGN) following foetal alcohol exposure (FAE) in infant subjects. Layer volume and total number of neurons and glia in the LGN of the FAE subjects were not significantly different from age-matched control subjects. The M neuronal soma size of FAE subjects, however, was significantly reduced to resemble the size of the P-neurons. These results suggest that alterations at the level of morphology and anatomy of the M-neurons may lead to behavioural deficits associated with the integrity of the dorsal visual pathway.

Depletion of Smarcb1 activates the Myc network of signalling cascades, increasing protein metabolism and activation of survival pathways allowing highly aggressive Kras-independent pancreatic cancer cells to develop. Blocking mesenchymal subpopulations in pancreatic cancer In pancreatic cancer models driven by Kras mutations, the authors find that a subpopulation of cancer cells can become independent of Kras signalling and instead acquire a mesenchymal phenotype driven by a Smarcb1–Myc network. This change is associated with an increase in protein metabolism, inhibition of which renders tumours sensitive to inhibition of this metabolic adaptation. These findings suggest a potential strategy for treating pancreatic cancer. Malignant neoplasms evolve in response to changes in oncogenic signalling 1 . Cancer cell plasticity in response to evolutionary pressures is fundamental to tumour progression and the development of therapeutic resistance 2 , 3 . Here we determine the molecular and cellular mechanisms of cancer cell plasticity in a conditional oncogenic Kras mouse model of pancreatic ductal adenocarcinoma (PDAC), a malignancy that displays considerable phenotypic diversity and morphological heterogeneity. In this model, stochastic extinction of oncogenic Kras signalling and emergence of Kras -independent escaper populations (cells that acquire oncogenic properties) are associated with de-differentiation and aggressive biological behaviour. Transcriptomic and functional analyses of Kras -independent escapers reveal the presence of Smarcb1 – Myc -network-driven mesenchymal reprogramming and independence from MAPK signalling. A somatic mosaic model of PDAC, which allows time-restricted perturbation of cell fate, shows that depletion of Smarcb1 activates the Myc network, driving an anabolic switch that increases protein metabolism and adaptive activation of endoplasmic-reticulum-stress-induced survival pathways. Increased protein turnover renders mesenchymal sub-populations highly susceptible to pharmacological and genetic perturbation of the cellular proteostatic machinery and the IRE1-α–MKK4 arm of the endoplasmic-reticulum-stress-response pathway. Specifically, combination regimens that impair the unfolded protein responses block the emergence of aggressive mesenchymal subpopulations in mouse and patient-derived PDAC models. These molecular and biological insights inform a potential therapeutic strategy for targeting aggressive mesenchymal features of PDAC.

Increasing evidence points to a role for antibody-mediated effector functions in preventing and controlling HIV infection. However, less is known about how these antibody effector functions evolve following infection. Moreover, how the humoral immune response is naturally tuned to recruit the antiviral activity of the innate immune system, and the extent to which these functions aid in the control of infection, are poorly understood. Using plasma samples from 10 hyper-acute HIV-infected South African women, identified in Fiebig stage I (the FRESH cohort), systems serology was performed to evaluate the functional and biophysical properties of gp120-, gp41-, and p24- specific antibody responses during the first year of infection. Significant changes were observed in both the functional and biophysical characteristics of the humoral immune response following acute HIV infection. Antibody Fc-functionality increased over the course of infection, with increases in antibody-mediated phagocytosis, NK activation, and complement deposition occurring in an antigen-specific manner. Changes in both antibody subclass and antibody Fc-glycosylation drove the evolution of antibody effector activity, highlighting natural modifications in the humoral immune response that may enable the directed recruitment of the innate immune system to target and control HIV. Moreover, enhanced antibody functionality, particularly gp120-specific polyfunctionality, was tied to improvements in clinical course of infection, supporting a role for functional antibodies in viral control.

The prediction of the response of infilled frames through the simplified approach of substituting the infill with an equivalent pin-jointed strut is treated. In this framework the results of an experimental study for the mechanical characterization of different types of masonry infills having the aim of estimating strength, Young modulus and Poisson’s ratio are presented. Four types of masonry were investigated and subjected to ordinary compressive tests orthogonally to the mortar beds and along the directions of the mortar beds. The experimental campaign confirmed the possibility of using an orthotropic plate model for prediction of the Poisson’s ratio and Young modulus along the diagonal direction of infills (these parameters are requested by a model already known in the literature for the identification of struts equivalent to masonry infills). The experimental campaign made it possible to recognise a correlation between the Poisson’s ratios and the strengths of masonries investigated along the orthotropic axes and to obtain the diagonal Poisson’s ratio without specific experimental tests. Finally, the experimental responses of some infilled frames were used to test the reliability of the model proposed here.

The mitogen-activated protein (MAP) kinases Erk-1 and Erk-2 are proline-directed kinases that are themselves activated through concomitant phosphorylation of tyrosine and threonine residues. The kinase p54 (M(r) 54,000), which was first isolated from cycloheximide-treated rats, is proline-directed like Erks-1/2, and requires both Tyr and Ser/Thr phosphorylation for activity. p54 is, however, distinct from Erks-1/2 in its substrate specificity, being unable to phosphorylate pp90rsk but more active in phosphorylating the c-Jun transactivation domain. Molecular cloning of p54 reveals a unique subfamily of extracellularly regulated kinases. Although they are 40-45% identical in sequence to Erks-1/2, unlike Erks-1/2 the p54s are only poorly activated in most cells by mitogens or phorbol esters. However, p54s are the principal c-Jun N-terminal kinases activated by cellular stress and tumour necrosis factor (TNF)-alpha, hence they are designated stress-activated protein kinases, or SAPKs. SAPKs are also activated by sphingomyelinase, which elicits a subset of cellular responses to TNF-alpha (ref. 9). SAPKs therefore define a new TNF-alpha and stress-activated signalling pathway, possibly initiated by sphingomyelin-based second messengers, which regulates the activity of c-Jun.

THE normal cellular homologue of the acutely transforming oncogene v-ra/is c- raf -l, which encodes a serine/threonine protein kinase that is activated by many extracellular stimuli 1 . The physiological substrates of the protein c-Raf-1 are unknown. The mitogen-activated protein (MAP) kinases ErkI and 2 are also activated by mitogens through phosphorylation of Erk tyrosine and threonine residues catalysed by a protein kinase of relative molecular mass 50,000, MAP kinase-kinase (MAPK-K) 2–7 . Here we report that MAPK-K as well as Erkl and 2 are constitutively active in v- raf -transformed cells. MAPK-K partially purified from v-raf-transformed cells or from mitogen-treated cells 3 can be deactivated by phosphatase 2A. c-Raf-1 purified after mitogen stimulation can reactivate the phosphatase 2A-inactivated MAPK-K over 30-fold in vitro. c-Raf-1 reactivation of MAPK-K coincides with the selective phosphorylation at serine/threonine residues of a polypeptide with M r 50,000 which coelutes precisely on cation-exchange chromatography with the MAPK-K activatable by c-Raf-1. These results indicate that c-Raf-1 is an immediate upstream activator of MAPK-K in vivo. To our knowledge, MAPK-K is the first physiological substrate of the c- raf -l protooncogene product to be identified.