Influenza virus differentially activates mTORC1 and mTORC2 signaling to maximize late stage replication

<div><p>Influenza A virus usurps host signaling factors to regulate its replication. One example is mTOR, a cellular regulator of protein synthesis, growth and motility. While the role of mTORC1 in viral infection has been studied, the mechanisms that induce mTORC1 activation and the substrates regulated by mTORC1 during influenza virus infection have not been established. In addition, the role of mTORC2 during influenza virus infection remains unknown. Here we show that mTORC2 and PDPK1 differentially phosphorylate AKT upon influenza virus infection. PDPK1-mediated phoshorylation of AKT at a distinct site is required for mTORC1 activation by influenza virus. On the other hand, the viral NS1 protein promotes phosphorylation of AKT at a different site via mTORC2, which is an activity dispensable for mTORC1 stimulation but known to regulate apoptosis. Influenza virus HA protein and down-regulation of the mTORC1 inhibitor REDD1 by the virus M2 protein promote mTORC1 activity. Systematic phosphoproteomics analysis performed in cells lacking the mTORC2 component Rictor in the absence or presence of Torin, an inhibitor of both mTORC1 and mTORC2, revealed mTORC1-dependent substrates regulated during infection. Members of pathways that regulate mTORC1 or are regulated by mTORC1 were identified, including constituents of the translation machinery that once activated can promote translation. mTORC1 activation supports viral protein expression and replication. As mTORC1 activation is optimal midway through the virus life cycle, the observed effects on viral protein expression likely support the late stages of influenza virus replication when infected cells undergo significant stress.</p></div

Sustained Stable Disease with Capecitabine plus Bevacizumab in Metastatic Appendiceal Adenocarcinoma: A Case Report.

In a patient who had been diagnosed in 2006 with appendiceal adenocarcinoma with peritoneal metastases after an incomplete surgery, palliative chemotherapy was administered. First-line treatment with 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) and second-line treatment including 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) plus panitumumab showed inefficiency in controlling disease progression. Third-line chemotherapy combining capecitabine plus bevacizumab was started, achieving good control of the tumour growth and a minor response in the second computed tomography scan. We decided to maintain the treatment, although forced bevacizumab "breaks" were necessary due to unexpected adverse events, with the patient suffering disease progression every time bevacizumab was stopped and reaching minor response again once the antiangiogenic treatment was reintroduced. During more than 10 years after starting third-line treatment, the patient maintained good performance status and disease stability with this "up and down" management until January 2019, when a neurological adverse event during bevacizumab infusion drove us to abandon it definitely

Assessing thoraco‐pelvic covariation in Homo sapiens and Pan troglodytes: A 3D geometric morphometric approach

Objectives Understanding thoraco‐pelvic integration in Homo sapiens and their closest living relatives (genus Pan) is of great importance within the context of human body shape evolution. However, studies assessing thoraco‐pelvic covariation across Hominoidea species are scarce, although recent research would suggest shared covariation patterns in humans and chimpanzees but also species‐specific features, with sexual dimorphism and allometry influencing thoraco‐pelvic covariation in these taxa differently. Material and Methods N = 30 adult H. sapiens and N = 10 adult Pan troglodytes torso 3D models were analyzed using 3D geometric morphometrics and linear measurements. Effects of sexual dimorphism and allometry on thoraco‐pelvic covariation were assessed via regression analyses, and patterns of thoraco‐pelvic covariation in humans and chimpanzees were computed via Two‐Block Partial Least Squares analyses. Results Results confirm the existence of common aspects of thoraco‐pelvic covariation in humans and chimpanzees, and also species‐specific covariation in H. sapiens that is strongly influenced by sexual dimorphism and allometry. Species‐specific covariation patterns in chimpanzees could not be confirmed because of the small sample size, but metrics point to a correspondence between the most caudal ribs and iliac crest morphology that would be irrespective of sex. Conclusions This study suggests that humans and chimpanzees share common aspects of thoraco‐pelvic covariation but might differ in others. In humans, torso integration is strongly influenced by sexual dimorphism and allometry, whilst in chimpanzees it may not be. This study also highlights the importance not only of torso widths but also of torso depths when describing patterns of thoraco‐pelvic covariation in primates. Larger samples are necessary to support these interpretations

Kolmogorov turbulence, Anderson localization and KAM integrability

The conditions for emergence of Kolmogorov turbulence, and related weak wave turbulence, in finite size systems are analyzed by analytical methods and numerical simulations of simple models. The analogy between Kolmogorov energy flow from large to small spacial scales and conductivity in disordered solid state systems is proposed. It is argued that the Anderson localization can stop such an energy flow. The effects of nonlinear wave interactions on such a localization are analyzed. The results obtained for finite size system models show the existence of an effective chaos border between the Kolmogorov-Arnold-Moser (KAM) integrability at weak nonlinearity, when energy does not flow to small scales, and developed chaos regime emerging above this border with the Kolmogorov turbulent energy flow from large to small scales.Comment: 8 pages, 6 figs, EPJB style

A novel hydrographic gridded data set for the northern Antarctic Peninsula

The northern Antarctic Peninsula (NAP) is a highly dynamic transitional zone between the subpolarpolar and oceanic-coastal environments, and it is located in an area affected by intense climate change, including intensification and spatial shifts of the westerlies as well as atmospheric and oceanic warming. In the NAP area, the water masses originate mainly from the Bellingshausen and Weddell seas, which create a marked regional dichotomy thermohaline characteristic. Although the NAP area has relatively easy access when compared to other Southern Ocean environments, our understanding of the water masses distribution and the dynamical processes affecting the variability of the region is still limited. That limitation is closely linked to the sparse data coverage, as is commonly the case in most Southern Ocean environments. This work provides a novel seasonal three-dimensional high-resolution hydrographic gridded data set for the NAP (version 1), namely the NAPv1.0. Hydrographic measurements from 1990 to 2019 comprising data collected by conductivity, temperature, depth (CTD) casts; sensors from the Marine Mammals Exploring the Oceans Pole to Pole (MEOP) consortium; and Argo floats have been optimally interpolated to produce maps of in situ temperature, practical salinity, and dissolved oxygen at 10 km spatial resolution and 90 depth levels. The water masses and oceanographic features in this regional gridded product are more accurate than other climatologies and state estimate products currently available. The data sets are available in netCDF format at https://doi.org/10.5281/zenodo.4420006 (Dotto et al., 2021). The novel and comprehensive data sets presented here for the NAPv1.0 product are a valuable tool to be used in studies addressing climatological changes in the unique NAP region since they provide accurate initial conditions for ocean models and improve the end of the 20th-And early 21st-century ocean mean-state representation for that area

Primary malignant melanoma of the biliary tract: A case report and literature review

BACKGROUND: Primary malignant melanoma of the biliary tract (MBT) is a rare condition whose diagnosis requires excluding a primary origin in another location. This paper reviews the most important characteristics of MBT cases published in the literature and reports a new case. The patient reported here is the first case of primary malignant melanoma of the biliary tract with pulmonary metastasis treated with immunotherapy. This patient remains disease-free 36 mo after the treatment of metastatic lung lesions. CASE SUMMARY: A 51-year-old man was admitted to the gastrointestinal department to study obstructive jaundice of a 1 wk clinical course. Magnetic resonance cholangiopancreatography revealed dilatation of the intrahepatic biliary tract and stenosis of the common hepatic duct. Given the suspicion of biliary tract neoplasia, cholecystectomy and resection of the common hepatic duct were performed with hepatic jejunostomy free of complications. Anatomo-pathological diagnosis was melanoma. After intervention, the patient was referred to the Department of Medical Oncology, where a primary origin was excluded in the skin, mucosa, and eyes. This confirmed diagnosis of primary biliary tract melanoma. Computed tomography was performed 12 mo after the procedure revealed several subcentimetric lung nodules. Wedge resection was performed. After confirming the diagnosis of pulmonary metastasis of primary melanoma of the biliary tract, the patient was started on immunotherapy with nivolumab. Tolerance to treatment was excellent. The patient remains disease-free 36 mo after the treatment of metastatic lung lesions. CONCLUSION: The patient reported here is the first case of primary malignant melanoma of the biliary tract with lung metastases successfully treated with immunotherapy

The exonuclease Xrn1 activates transcription and translation of mRNAs encoding membrane proteins

The highly conserved 5'-3' exonuclease Xrn1 regulates gene expression in eukaryotes by coupling nuclear DNA transcription to cytosolic mRNA decay. By integrating transcriptome-wide analyses of translation with biochemical and functional studies, we demonstrate an unanticipated regulatory role of Xrn1 in protein synthesis. Xrn1 promotes translation of a specific group of transcripts encoding membrane proteins. Xrnl-dependence for translation is linked to poor structural RNA contexts for translation initiation, is mediated by interactions with components of the translation initiation machinery and correlates with an Xrnl-dependence for mRNA localization at the endoplasmic reticulum, the translation compartment of membrane proteins. Importantly, for this group of mRNAs, Xrn1 stimulates transcription, mRNA translation and decay. Our results uncover a crosstalk between the three major stages of gene expression coordinated by Xrn1 to maintain appropriate levels of membrane proteins

The Green Bank Northern Celestial Cap Pulsar Survey - I: Survey Description, Data Analysis, and Initial Results

We describe an ongoing search for pulsars and dispersed pulses of radio emission, such as those from rotating radio transients (RRATs) and fast radio bursts (FRBs), at 350 MHz using the Green Bank Telescope. With the Green Bank Ultimate Pulsar Processing Instrument, we record 100 MHz of bandwidth divided into 4,096 channels every 81.92 $\mu s$. This survey will cover the entire sky visible to the Green Bank Telescope ($\delta > -40^\circ$, or 82% of the sky) and outside of the Galactic Plane will be sensitive enough to detect slow pulsars and low dispersion measure ($<$30 $\mathrm{pc\,cm^{-3}}$) millisecond pulsars (MSPs) with a 0.08 duty cycle down to 1.1 mJy. For pulsars with a spectral index of $-$1.6, we will be 2.5 times more sensitive than previous and ongoing surveys over much of our survey region. Here we describe the survey, the data analysis pipeline, initial discovery parameters for 62 pulsars, and timing solutions for 5 new pulsars. PSR J0214$+$5222 is an MSP in a long-period (512 days) orbit and has an optical counterpart identified in archival data. PSR J0636$+$5129 is an MSP in a very short-period (96 minutes) orbit with a very low mass companion (8 $M_\mathrm{J}$). PSR J0645$+$5158 is an isolated MSP with a timing residual RMS of 500 ns and has been added to pulsar timing array experiments. PSR J1434$+$7257 is an isolated, intermediate-period pulsar that has been partially recycled. PSR J1816$+$4510 is an eclipsing MSP in a short-period orbit (8.7 hours) and may have recently completed its spin-up phase.Comment: 18 pages, 10 figures, 5 tables, accepted by Ap

A palaeoecological approach to understanding the past and present of Sierra Nevada, a Southwestern European biodiversity hotspot

Mediterranean mountainous environments are biodiversity hotspots and priority areas in conservation agendas. Although they are fragile and threatened by forecasted global change scenarios, their sensitivity to long-term environmental variability is still understudied. The Sierra Nevada range, located in southern Spain on the north-western European flanks of the Mediterranean basin, is a biodiversity hotspot. Consequently, Sierra Nevada provides an excellent model system to apply a palaeoecological approach to detect vegetation changes, explore the drivers triggering those changes, and how vegetation changes link to the present landscape in such a paradigmatic mountain system. A multi-proxy strategy (magnetic susceptibility, grain size, loss-on-ignition, macroremains, charcoal and palynological analyses) is applied to an 8400-year long lacustrine environmental archive from the Laguna de la Mosca (2889 masl). The long-term ecological data show how the Early Holocene pine forests transitioned towards mixed Pinus-Quercus submediterranean forests as a response to a decrease in seasonality at ~7.3 cal. kyr BP. The mixed Pinus-Quercus submediterranean forests collapsed drastically giving way to open evergreen Quercus formations at ~4.2 cal. kyr BP after a well-known aridity crisis. Under the forecasted northward expansion of the Mediterranean area due to global change-related aridity increase, mountain forests inhabiting territories adjacent to the Mediterranean Region could experience analogous responses to those detected in the Sierra Nevada forests to the Mid to Late Holocene aridification, moving from temperate to submediterranean and then Mediterranean formations