Topology of molecular machines of the endoplasmic reticulum: a compilation of proteomics and cytological data

The endoplasmic reticulum (ER) is a key organelle of the secretion pathway involved in the synthesis of both proteins and lipids destined for multiple sites within and without the cell. The ER functions to both co- and post-translationally modify newly synthesized proteins and lipids and sort them for housekeeping within the ER and for transport to their sites of function away from the ER. In addition, the ER is involved in the metabolism and degradation of specific xenobiotics and endogenous biosynthetic products. A variety of proteomics studies have been reported on different subcompartments of the ER providing an ER protein dictionary with new data being made available on many protein complexes of relevance to the biology of the ER including the ribosome, the translocon, coatomer proteins, cytoskeletal proteins, folding proteins, the antigen-processing machinery, signaling proteins and proteins involved in membrane traffic. This review examines proteomics and cytological data in support of the presence of specific molecular machines at specific sites or subcompartments of the ER

Metabolic alterations during the growth of tumour spheroids

Solid tumours undergo considerable alterations in their metabolism of nutrients in order to generate sufficient energy and biomass for sustained growth and proliferation. During growth, the tumour microenvironment exerts a number of influences (e.g. hypoxia and acidity) that affect cellular biology and the flux or utilisation of fuels including glucose. The tumour spheroid model was used to characterise the utilisation of glucose and describe alterations to the activity and expression of key glycolytic enzymes during the tissue growth curve. Glucose was avidly consumed and associated with the production of lactate and an acidified medium, confirming the reliance on glycolytic pathways and a diminution of oxidative phosphorylation. The expression levels and activities of hexokinase, phosphofructokinase-1, pyruvate kinase and lactate dehydrogenase in the glycolytic pathway were measured to assess glycolytic capacity. Similar measurements were made for glucose-6-phosphate dehydrogenase, the entry point and regulatory step of the pentose-phosphate pathway (PPP) and for cytosolic malate dehydrogenase, a key link to TCA cycle intermediates. The parameters for these key enzymes were shown to undergo considerable variation during the growth curve of tumour spheroids. In addition, they revealed that the dynamic alterations were influenced by both transcriptional and posttranslational mechanisms

Metabolic alterations during the growth of tumour spheroids

Solid tumours undergo considerable alterations in their metabolism of nutrients in order to generate sufficient energy and biomass for sustained growth and proliferation. During growth, the tumour microenvironment exerts a number of influences (e.g. hypoxia and acidity) that affect cellular biology and the flux or utilisation of fuels including glucose. The tumour spheroid model was used to characterise the utilisation of glucose and describe alterations to the activity and expression of key glycolytic enzymes during the tissue growth curve. Glucose was avidly consumed and associated with the production of lactate and an acidified medium, confirming the reliance on glycolytic pathways and a diminution of oxidative phosphorylation. The expression levels and activities of hexokinase, phosphofructokinase-1, pyruvate kinase and lactate dehydrogenase in the glycolytic pathway were measured to assess glycolytic capacity. Similar measurements were made for glucose-6-phosphate dehydrogenase, the entry point and regulatory step of the pentose-phosphate pathway (PPP) and for cytosolic malate dehydrogenase, a key link to TCA cycle intermediates. The parameters for these key enzymes were shown to undergo considerable variation during the growth curve of tumour spheroids. In addition, they revealed that the dynamic alterations were influenced by both transcriptional and posttranslational mechanisms

Corporate Entrepreneurship:From Structures to Mindset

Corporate entrepreneurship dispersed throughout an organization and leveraging the entrepreneurial potential of all its employees bears significant benefits for those organizations that embrace it. However, it appears more difficult to instill and requires strong investment in the development of human capital and entrepreneurial mindset among the employees and across the organization. In this chapter, we discuss the essence of corporate entrepreneurship mindset and show that across an organization, there might be different entrepreneurial mindsets that correspond to different people, opportunities, and contexts. Although different, they all lead to enactment of entrepreneurial projects. This chapter, thus, contributes to the discussion regarding the nature of corporate entrepreneurial mindsets, and their development and stimulation within an organization, from both academic and practical view

European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment

To develop a European guideline on pharmacologic treatment of Tourette syndrome (TS) the available literature was thoroughly screened and extensively discussed by a working group of the European Society for the Study of Tourette syndrome (ESSTS). Although there are many more studies on pharmacotherapy of TS than on behavioral treatment options, only a limited number of studies meets rigorous quality criteria. Therefore, we have devised a two-stage approach. First, we present the highest level of evidence by reporting the findings of existing Cochrane reviews in this field. Subsequently, we provide the first comprehensive overview of all reports on pharmacological treatment options for TS through a MEDLINE, PubMed, and EMBASE search for all studies that document the effect of pharmacological treatment of TS and other tic disorders between 1970 and November 2010. We present a summary of the current consensus on pharmacological treatment options for TS in Europe to guide the clinician in daily practice. This summary is, however, rather a status quo of a clinically helpful but merely low evidence guideline, mainly driven by expert experience and opinion, since rigorous experimental studies are scarce

Cosmological Fast Optical Transients with the Zwicky Transient Facility: A Search for Dirty Fireballs

Dirty fireballs are a hypothesized class of relativistic massive-star explosions with an initial Lorentz factor Γinit below the Γinit ∼ 100 required to produce a long-duration gamma-ray burst (LGRB), but which could still produce optical emission resembling LGRB afterglows. Here we present the results of a search for on-axis optical afterglows using the Zwicky Transient Facility (ZTF). Our search yielded seven optical transients that resemble on-axis LGRB afterglows in terms of their red colors (g − r > 0 mag), faint host galaxies (r > 23 mag), rapid fading (dr/dt > 1 mag day−1), and in some cases X-ray and radio emission. Spectroscopy of the transient emission within a few days of discovery established cosmological distances (redshift z = 0.876 to 2.9) for six of the seven events, tripling the number of afterglows with redshift measurements discovered by optical surveys without a γ-ray trigger. A likely associated LGRB (GRB 200524A, GRB 210204A, GRB 210212B, and GRB 210610B) was identified for four events (ZTF 20abbiixp/AT 2020kym, ZTF 21aagwbjr/AT 2021buv, ZTF 21aakruew/AT 2021cwd, and ZTF 21abfmpwn/AT 2021qbd) post facto, while three (ZTF 20aajnksq/AT 2020blt, ZTF 21aaeyldq/AT 2021any, and ZTF 21aayokph/AT 2021lfa) had no detected LGRB counterpart. The simplest explanation for the three “orphan” events is that they were regular LGRBs missed by high-energy satellites owing to detector sensitivity and duty cycle, although it is possible that they were intrinsically subluminous in γ-rays or viewed slightly off-axis. We rule out a scenario in which dirty fireballs have a similar energy per solid angle to LGRBs and are an order of magnitude more common. In addition, we set the first direct constraint on the ratio of the opening angles of the material producing γ-rays and the material producing early optical afterglow emission, finding that they must be comparable

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Measurement of ZZ production in leptonic final states at {\surd}s of 1.96 TeV at CDF

In this paper we present a precise measurement of the total ZZ production cross section in pp collisions at {\surd}s= 1.96 TeV, using data collected with the CDF II detector corresponding to an integrated luminosity of approximately 6 fb-1. The result is obtained by combining separate measurements in the four-charged (lll'l'), and two-charged-lepton and two-neutral-lepton (llvv) decay modes of the Z. The combined measured cross section for pp {\to} ZZ is 1.64^(+0.44)_(-0.38) pb. This is the most precise measurement of the ZZ production cross section in 1.96 TeV pp collisions to date.Comment: submitted to Phys. Rev. Let

Localization and broadband follow-up of the gravitational-wave transient GW150914

A gravitational-wave (GW) transient was identified in data recorded by the Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) detectors on 2015 September 14. The event, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the GW data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network circulars, giving an overview of the participating facilities, the GW sky localization coverage, the timeline, and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic (EM) signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the EM data and results of the EM follow-up campaign are being disseminated in papers by the individual teams

A blast from the infant Universe: The very high- z GRB 210905A

We present a detailed follow-up of the very energetic GRB 210905A at a high redshift of z=6.312 and its luminous X-ray and optical afterglow. Following the detection by Swift and Konus-Wind, we obtained a photometric and spectroscopic follow-up in the optical and near-infrared (NIR), covering both the prompt and afterglow emission from a few minutes up to 20 Ms after burst. With an isotropic gamma-ray energy release of Eiso = 1.270.19+0.20- 1054 erg, GRB 210905A lies in the top 7% of gamma-ray bursts (GRBs) in the Konus-Wind catalogue in terms of energy released. Its afterglow is among the most luminous ever observed, and, in particular, it is one of the most luminous in the optical at t0.5 d in the rest frame. The afterglow starts with a shallow evolution that can be explained by energy injection, and it is followed by a steeper decay, while the spectral energy distribution is in agreement with slow cooling in a constant-density environment within the standard fireball theory. A jet break at 46.2 16.3 d (6.3±2.2 d rest-frame) has been observed in the X-ray light curve; however, it is hidden in the H band due to a constant contribution from the host galaxy and potentially from a foreground intervening galaxy. In particular, the host galaxy is only the fourth GRB host at z>6 known to date. By assuming a number density n=1 cm3 and an efficiency η=0.2, we derived a half-opening angle of 8.4±1.0, which is the highest ever measured for a z6 burst, but within the range covered by closer events. The resulting collimation-corrected gamma-ray energy release of 1- 1052 erg is also among the highest ever measured. The moderately large half-opening angle argues against recent claims of an inverse dependence of the half-opening angle on the redshift. The total jet energy is likely too large to be sustained by a standard magnetar, and it suggests that the central engine of this burst was a newly formed black hole. Despite the outstanding energetics and luminosity of both GRB 210905A and its afterglow, we demonstrate that they are consistent within 2 with those of less distant bursts, indicating that the powering mechanisms and progenitors do not evolve significantly with redshift