Participation of the Cell Polarity Protein PALS1 to T-Cell Receptor-Mediated NF-κB Activation

BACKGROUND: Beside their established function in shaping cell architecture, some cell polarity proteins were proposed to participate to lymphocyte migration, homing, scanning, as well as activation following antigen receptor stimulation. Although PALS1 is a central component of the cell polarity network, its expression and function in lymphocytes remains unknown. Here we investigated whether PALS1 is present in T cells and whether it contributes to T Cell-Receptor (TCR)-mediated activation. METHODOLOGY/PRINCIPAL FINDINGS: By combining RT-PCR and immunoblot assays, we found that PALS1 is constitutively expressed in human T lymphocytes as well as in Jurkat T cells. siRNA-based knockdown of PALS1 hampered TCR-induced activation and optimal proliferation of lymphocyte. We further provide evidence that PALS1 depletion selectively hindered TCR-driven activation of the transcription factor NF-κB. CONCLUSIONS: The cell polarity protein PALS1 is expressed in T lymphocytes and participates to the optimal activation of NF-κB following TCR stimulation

Neural Correlates of Threat Perception: Neural Equivalence of Conspecific and Heterospecific Mobbing Calls Is Learned

Songbird auditory areas (i.e., CMM and NCM) are preferentially activated to playback of conspecific vocalizations relative to heterospecific and arbitrary noise [1]–[2]. Here, we asked if the neural response to auditory stimulation is not simply preferential for conspecific vocalizations but also for the information conveyed by the vocalization. Black-capped chickadees use their chick-a-dee mobbing call to recruit conspecifics and other avian species to mob perched predators [3]. Mobbing calls produced in response to smaller, higher-threat predators contain more “D” notes compared to those produced in response to larger, lower-threat predators and thus convey the degree of threat of predators [4]. We specifically asked whether the neural response varies with the degree of threat conveyed by the mobbing calls of chickadees and whether the neural response is the same for actual predator calls that correspond to the degree of threat of the chickadee mobbing calls. Our results demonstrate that, as degree of threat increases in conspecific chickadee mobbing calls, there is a corresponding increase in immediate early gene (IEG) expression in telencephalic auditory areas. We also demonstrate that as the degree of threat increases for the heterospecific predator, there is a corresponding increase in IEG expression in the auditory areas. Furthermore, there was no significant difference in the amount IEG expression between conspecific mobbing calls or heterospecific predator calls that were the same degree of threat. In a second experiment, using hand-reared chickadees without predator experience, we found more IEG expression in response to mobbing calls than corresponding predator calls, indicating that degree of threat is learned. Our results demonstrate that degree of threat corresponds to neural activity in the auditory areas and that threat can be conveyed by different species signals and that these signals must be learned

The Baculovirus Uses a Captured Host Phosphatase to Induce Enhanced Locomotory Activity in Host Caterpillars

The baculovirus is a classic example of a parasite that alters the behavior or physiology of its host so that progeny transmission is maximized. Baculoviruses do this by inducing enhanced locomotory activity (ELA) that causes the host caterpillars to climb to the upper foliage of plants. We previously reported that this behavior is not induced in silkworms that are infected with a mutant baculovirus lacking its protein tyrosine phosphatase (ptp) gene, a gene likely captured from an ancestral host. Here we show that the product of the ptp gene, PTP, associates with baculovirus ORF1629 as a virion structural protein, but surprisingly phosphatase activity associated with PTP was not required for the induction of ELA. Interestingly, the ptp knockout baculovirus showed significantly reduced infectivity of larval brain tissues. Collectively, we show that the modern baculovirus uses the host-derived phosphatase to establish adequate infection for ELA as a virion-associated structural protein rather than as an enzyme

Frenotomy with breastfeeding support versus breastfeeding support alone for infants with tongue-tie and breastfeeding difficulties: the FROSTTIE RCT

BackgroundTongue-tie can be diagnosed in 3–11% of babies, with some studies reporting almost universal breastfeeding difficulties, and others reporting very few feeding difficulties that relate to the tongue-tie itself, instead noting that incorrect positioning and attachment are the primary reasons behind the observed breastfeeding difficulties and not the tongue-tie itself. The only existing trials of frenotomy are small and underpowered and/or include only very short-term or subjective outcomes.ObjectiveTo investigate whether frenotomy is clinically and cost-effective to promote continuation of breastfeeding at 3 months in infants with breastfeeding difficulties diagnosed with tongue-tie.DesignA multicentre, unblinded, randomised, parallel group controlled trial.SettingTwelve infant feeding services in the UK.ParticipantsInfants aged up to 10 weeks referred to an infant feeding service (by a parent, midwife or other breastfeeding support service) with breastfeeding difficulties and judged to have tongue-tie.InterventionsInfants were randomly allocated to frenotomy with standard breastfeeding support or standard breastfeeding support without frenotomy.Main outcome measuresPrimary outcome was any breastmilk feeding at 3 months according to maternal self-report. Secondary outcomes included mother’s pain, exclusive breastmilk feeding, exclusive direct breastfeeding, frenotomy, adverse events, maternal anxiety and depression, maternal and infant NHS health-care resource use, cost-effectiveness, and any breastmilk feeding at 6 months of age.ResultsBetween March 2019 and November 2020, 169 infants were randomised, 80 to the frenotomy with breastfeeding support arm and 89 to the breastfeeding support arm from a planned sample size of 870 infants. The trial was stopped in the context of the COVID-19 pandemic due to withdrawal of breastfeeding support services, slow recruitment and crossover between arms. In the frenotomy with breastfeeding support arm 74/80 infants (93%) received their allocated intervention, compared to 23/89 (26%) in the breastfeeding support arm. Primary outcome data were available for 163/169 infants (96%). There was no evidence of a difference between the arms in the rate of breastmilk feeding at 3 months, which was high in both groups (67/76, 88% vs. 75/87, 86%; adjusted risk ratio 1.02, 95% confidence interval 0.90 to 1.16). Adverse events were reported for three infants after surgery [bleeding (n = 1), salivary duct damage (n = 1), accidental cut to the tongue and salivary duct damage (n = 1)]. Cost-effectiveness could not be determined with the information available.LimitationsThe statistical power of the analysis was extremely limited due to not achieving the target sample size and the high proportion of infants in the breastfeeding support arm who underwent frenotomy.ConclusionsThis trial does not provide sufficient information to assess whether frenotomy in addition to breastfeeding support improves breastfeeding rates in infants diagnosed with tongue-tie.Future workThere is a clear lack of equipoise in the UK concerning the use of frenotomy, however, the effectiveness and cost-effectiveness of the procedure still need to be established. Other study designs will need to be considered to address this objective.Trial registrationThis trial is registered as ISRCTN 10268851

Human malarial disease: a consequence of inflammatory cytokine release

Malaria causes an acute systemic human disease that bears many similarities, both clinically and mechanistically, to those caused by bacteria, rickettsia, and viruses. Over the past few decades, a literature has emerged that argues for most of the pathology seen in all of these infectious diseases being explained by activation of the inflammatory system, with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Although not often expressed in energy terms, there is, when reduced to biochemical essentials, wide agreement that infection with falciparum malaria is often fatal because mitochondria are unable to generate enough ATP to maintain normal cellular function. Most, however, would contend that this largely occurs because sequestered parasitized red cells prevent sufficient oxygen getting to where it is needed. This review considers the evidence that an equally or more important way ATP deficency arises in malaria, as well as these other infectious diseases, is an inability of mitochondria, through the effects of inflammatory cytokines on their function, to utilise available oxygen. This activity of these cytokines, plus their capacity to control the pathways through which oxygen supply to mitochondria are restricted (particularly through directing sequestration and driving anaemia), combine to make falciparum malaria primarily an inflammatory cytokine-driven disease

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Drug discovery in advanced prostate cancer: translating biology into therapy.

Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis and poses considerable therapeutic challenges. Recent genetic and technological advances have provided insights into prostate cancer biology and have enabled the identification of novel drug targets and potent molecularly targeted therapeutics for this disease. In this article, we review recent advances in prostate cancer target identification for drug discovery and discuss their promise and associated challenges. We review the evolving therapeutic landscape of CRPC and discuss issues associated with precision medicine as well as challenges encountered with immunotherapy for this disease. Finally, we envision the future management of CRPC, highlighting the use of circulating biomarkers and modern clinical trial designs

Treasures from the prose writings of John Milton ...

viii, 486 p. front. (port.) 19 cm.Preface signed: Fayette Hurd."A list of Milton's prose works. Arranged in chronological order": p.[467]-472

Letters on chivalry and romance (1762)

Mode of access: Internet