The N-terminal region of the ubiquitin regulatory x (UBX) domain-containing Protein 1 (UBXD1) modulates interdomain communication within the valosin-containing Protein p97

Valosin-containing protein/p97 is an ATP-driven protein segregase that cooperates with distinct protein cofactors to control various aspects of cellular homeostasis. Mutations at the interface between the regulatory N-domain and the first of two ATPase domains (D1 and D2) deregulate the ATPase activity and cause a multisystem degenerative disorder, inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia/amyotrophic lateral sclerosis. Intriguingly, the mutations affect only a subset of p97-mediated pathways correlating with unbalanced cofactor interactions and most prominently compromised binding of the ubiquitin regulatory X domain-containing protein 1 (UBXD1) cofactor during endolysosomal sorting of caveolin-1. However, how the mutations impinge on the p97-cofactor interplay is unclear so far. In cell-based endosomal localization studies, we identified a critical role of the N-terminal region of UBXD1 (UBXD1-N). Biophysical studies using NMR and CD spectroscopy revealed that UBXD1-N can be classified as intrinsically disordered. NMR titration experiments confirmed a valosin-containing protein/p97 interaction motif and identified a second binding site at helices 1 and 2 of UBXD1-N as binding interfaces for p97. In reverse titration experiments, we identified two distant epitopes on the p97 N-domain that include disease-associated residues and an additional interaction between UBXD1-N and the D1D2 barrel of p97 that was confirmed by fluorescence anisotropy. Functionally, binding of UBXD1-N to p97 led to a reduction of ATPase activity and partial protection from proteolysis. These findings indicate that UBXD1-N intercalates into the p97-ND1 interface, thereby modulating interdomain communication of p97 domains and its activity with relevance for disease pathogenesis. We propose that the polyvalent binding mode characterized for UBXD1-N is a more general principle that defines a subset of p97 cofactors

Galleria melonella as an experimental in vivo host model for the fish-pathogenic oomycete Saprolegnia parasitica

Our work is supported by the University of Aberdeen (AW, PvW); BBSRC (BB/M026566/1 & BB/P020224/1: PvW); BBSRC (BB/N005058/1 & BB/J018333/1: FT & PvW); NERC (NE/P010873/1: PvW). We would like to acknowledge Joan Wilson and Bill Mathieson at NHS Grampian Biorepository (Aberdeen, Scotland) for help with histological experiments and Kevin McKenzie and his team at the Microscopy Core facility at the University of Aberdeen for assistance with microscopy and histology.Peer reviewedPublisher PD

Sequestration of defenses against predators drives specialized host plant associations in preadapted milkweed bugs (Heteroptera: Lygaeinae)

AbstractHost plant specialization across herbivorous insects varies dramatically, but while the molecular mechanisms of host plant adaptations are increasingly known, we often lack a comprehensive understanding of the selective forces that favor specialization. The milkweed bugs (Heteroptera: Lygaeinae) are ancestrally associated with plants of the Apocynaceae from which they commonly sequester cardiac glycosides for defense, facilitated by resistant NaNa+/K+-ATPases and adaptations for transport, storage, and discharge of toxins. Here, we show that three Lygaeinae species independently colonized four novel nonapocynaceous hosts that convergently produce cardiac glycosides. A fourth species shifted to a new source of toxins by tolerating and sequestering alkaloids from meadow saffron (Colchicum autumnale, Colchicaceae). Across three milkweed bug species tested, feeding on seeds containing toxins did not improve growth or speed of development and even impaired growth and development in two species, but sequestration mediated protection of milkweed bugs against two natural predators: lacewing larvae and passerine birds. We conclude that physiological preadaptations and convergent phytochemistry facilitated novel specialized host associations. Since toxic seeds did not improve growth but either impaired growth or, at most, had neutral effects, selection by predators on sequestration of defenses, rather than the exploitation of additional profitable dietary resources, can lead to obligatory specialized host associations in otherwise generalist insects

20 ps Time Resolution with a Fully-Efficient Monolithic Silicon Pixel Detector without Internal Gain Layer

A second monolithic silicon pixel prototype was produced for the MONOLITH project. The ASIC contains a matrix of hexagonal pixels with 100 {\mu}m pitch, readout by a low-noise and very fast SiGe HBT frontend electronics. Wafers with 50 {\mu}m thick epilayer of 350 {\Omega}cm resistivity were used to produce a fully depleted sensor. Laboratory and testbeam measurements of the analog channels present in the pixel matrix show that the sensor has a 130 V wide bias-voltage operation plateau at which the efficiency is 99.8%. Although this prototype does not include an internal gain layer, the design optimised for timing of the sensor and the front-end electronics provides a time resolutions of 20 ps.Comment: 11 pages, 11 figure

Testbeam results of the Picosecond Avalanche Detector proof-of-concept prototype

The proof-of-concept prototype of the Picosecond Avalanche Detector, a multi-PN junction monolithic silicon detector with continuous gain layer deep in the sensor depleted region, was tested with a beam of 180 GeV pions at the CERN SPS. The prototype features low noise and fast SiGe BiCMOS frontend electronics and hexagonal pixels with 100 μm pitch. At a sensor bias voltage of 125 V, the detector provides full efficiency and average time resolution of 30, 25 and 17 ps in the overall pixel area for a power consumption of 0.4, 0.9 and 2.7 W/cm2, respectively. In this first prototype the time resolution depends significantly on the distance from the center of the pixel, varying at the highest power consumption measured between 13 ps at the center of the pixel and 25 ps in the inter-pixel region

Picosecond Avalanche Detector — working principle and gain measurement with a proof-of-concept prototype

The Picosecond Avalanche Detector is a multi-junction silicon pixel detector based on a (NP)drift(NP)gain structure, devised to enable charged-particle tracking with high spatial resolution and picosecond time-stamp capability. It uses a continuous junction deep inside the sensor volume to amplify the primary charge produced by ionizing radiation in a thin absorption layer. The signal is then induced by the secondary charges moving inside a thicker drift region. A proof-of-concept monolithic prototype, consisting of a matrix of hexagonal pixels with 100 μm pitch, has been produced using the 130 nm SiGe BiCMOS process by IHP microelectronics. Measurements on probe station and with a 55Fe X-ray source show that the prototype is functional and displays avalanche gain up to a maximum electron gain of 23. A study of the avalanche characteristics, corroborated by TCAD simulations, indicates that space-charge effects due to the large primary charge produced by the conversion of X-rays from the ^55Fe source limits the effective gain

Testbeam Results of the Picosecond Avalanche Detector Proof-Of-Concept Prototype

The proof-of-concept prototype of the Picosecond Avalanche Detector, a multi-PN junction monolithic silicon detector with continuous gain layer deep in the sensor depleted region, was tested with a beam of 180 GeV pions at the CERN SPS. The prototype features low noise and fast SiGe BiCMOS frontend electronics and hexagonal pixels with 100 {\mu}m pitch. At a sensor bias voltage of 125 V, the detector provides full efficiency and average time resolution of 30, 25 and 17 ps in the overall pixel area for a power consumption of 0.4, 0.9 and 2.7 W/cm^2, respectively. In this first prototype the time resolution depends significantly on the distance from the center of the pixel, varying at the highest power consumption measured between 13 ps at the center of the pixel and 25 ps in the inter-pixel region

Stereotypical Chronic Lymphocytic Leukemia B-Cell Receptors Recognize Survival Promoting Antigens on Stromal Cells

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Survival of CLL cells depends on their close contact with stromal cells in lymphatic tissues, bone marrow and blood. This microenvironmental regulation of CLL cell survival involves the stromal secretion of chemo- and cytokines as well as the expression of adhesion molecules. Since CLL survival may also be driven by antigenic stimulation through the B-cell antigen receptor (BCR), we explored the hypothesis that these processes may be linked to each other. We tested if stromal cells could serve as an antigen reservoir for CLL cells, thus promoting CLL cell survival by stimulation through the BCR. As a proof of principle, we found that two CLL BCRs with a common stereotyped heavy chain complementarity-determining region 3 (previously characterized as “subset 1”) recognize antigens highly expressed in stromal cells – vimentin and calreticulin. Both antigens are well-documented targets of autoantibodies in autoimmune disorders. We demonstrated that vimentin is displayed on the surface of viable stromal cells and that it is present and bound by the stereotyped CLL BCR in CLL-stroma co-culture supernatant. Blocking the vimentin antigen by recombinant soluble CLL BCR under CLL-stromal cell co-culture conditions reduces stroma-mediated anti-apoptotic effects by 20–45%. We therefore conclude that CLL BCR stimulation by stroma-derived antigens can contribute to the protective effect that the stroma exerts on CLL cells. This finding sheds a new light on the understanding of the pathobiology of this so far mostly incurable disease

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016