De novo design of bioactive protein switches.

Allosteric regulation of protein function is widespread in biology, but is challenging for de novo protein design as it requires the explicit design of multiple states with comparable free energies. Here we explore the possibility of designing switchable protein systems de novo, through the modulation of competing inter- and intramolecular interactions. We design a static, five-helix 'cage' with a single interface that can interact either intramolecularly with a terminal 'latch' helix or intermolecularly with a peptide 'key'. Encoded on the latch are functional motifs for binding, degradation or nuclear export that function only when the key displaces the latch from the cage. We describe orthogonal cage-key systems that function in vitro, in yeast and in mammalian cells with up to 40-fold activation of function by key. The ability to design switchable protein functions that are controlled by induced conformational change is a milestone for de novo protein design, and opens up new avenues for synthetic biology and cell engineering

Comparison and Uniqueness Results for the Periodic Boundary Value Problem for Linear First-Order Differential Equations Subject to a Functional Perturbation

This is a post-peer-review, pre-copyedit version of a chapter published in Area I. et al. (eds) Nonlinear Analysis and Boundary Value Problems. NABVP 2018. Springer Proceedings in Mathematics & Statistics, vol 292. Springer, Cham. The final authenticated version is available online at: https://doi.org/10.1007/978-3-030-26987-6_14We improve some comparison results for the periodic boundary value problem related to a first-order differential equation perturbed by a functional term. The comparison results presented cover many cases as differential equations with delay, differential equations with maxima and integro-differential equations. The interesting case of functional perturbation with piecewise constant arguments is also analyzed

New evidence for a massive black hole at the centre of the quiescent galaxy M32

Massive black holes are thought to reside at the centres of many galaxies, where they power quasars and active galactic nuclei. But most galaxies are quiescent, indicating that any central massive black hole present will be starved of fuel and therefore detectable only through its gravitational influence on the motions of the surrounding stars. M32 is a nearby, quiescent elliptical galaxy in which the presence of a black hole has been suspected; however, the limited resolution of the observational data and the restricted classes of models used to interpret this data have made it difficult to rule out alternative explanations, such as models with an anisotropic stellar velocity distribution and no dark mass or models with a central concentration of dark objects (for example, stellar remnants or brown dwarfs). Here we present high-resolution optical HST spectra of M32, which show that the stellar velocities near the centre of this galaxy exceed those inferred from previous ground-based observations. We use a range of general dynamical models to determine a central dark mass concentration of (3.4 +/- 1.6) x 10^6 solar masses, contained within a region only 0.3 pc across. This leaves a massive black hole as the most plausible explanation of the data, thereby strengthening the view that such black holes exist even in quiescent galaxies.Comment: 8 pages, LaTeX, 3 figures; mpeg animation of the stellar motions in M32 available at http://oposite.stsci.edu/pubinfo/Anim.htm

Heading towards an unsustainable world: some of the implications of not achieving the SDGs

The Sustainable Development Goals (SDGs) were conceived at the United Nations Conference on Sustainable Development, held in Rio de Janeiro in 2012 (Rio + 20), and adopted by the United Nations General Assembly in September 2015. They are part of a larger framework, namely the UN 2030 Agenda for Sustainable Development. Since then, many countries round the world have been engaging in respect of their implementation. The slow progress seen in the implementation of the SDGs, is in contrast with the many negative implications of not implementing them. This paper outlines the relevance of the SDGs, the barriers currently seen in respect of their implementation and outlines what is at stake, if they are not duly implemented. To accomplish this, a thorough literature review of contributions published in the field of SDGs in English between the years 2012–2020 was performed

Which symptoms are linked to a delayed presentation among melanoma patients? A retrospective study

Background: The incidence of melanoma is rising. Early detection is associated with a more favourable outcome. The factors that influence the timing of a patient’s presentation for medical assessment are not fully understood. The aims of the study were to measure the nature and duration of melanoma symptoms in a group of patients diagnosed with melanoma within the preceding 18 months and to identify the symptoms and barriers associated with a delay in presentation. Methods: A questionnaire was distributed to a random sample of 200 of the 963 melanoma patients who had participated in the Cancer Patient Experience Survey 2010 and were known to be alive 1 year later. Data were collected on symptoms, duration of symptoms prior to presentation and the reasons for not attending a doctor sooner. Results: A total of 159 patients responded to the questionnaire; 74 (47%) were men; mean age was 62 (range 24–90) years. Of the 149 patients who reported a symptom, 40 (27%) had a delayed presentation (i.e. >3 months). A mole growing bigger was the most common symptom and reporting this symptom was significantly associated with a delayed presentation (odds ratio (OR) 2.04, 95% confidence interval (95% CI) 1.14–5.08). Patients aged ≥65 years were less likely to report a barrier to presentation and were less likely to delay than those under 40, although this was of borderline statistical significance (OR 0.28, 95% CI 0.08–1.00). Conclusions: This study highlights that an enlarging mole is a significant symptom influencing the timing of presentation. Increasing public awareness of the signs of melanoma and of the importance of early presentation is desirable. Health professionals should take advantage of the opportunity to educate patients on such symptoms and signs where feasible. Further exploration of the barriers to presentation in younger people should be considered

Modulation of phosphofructokinase (PFK) from Setaria cervi, a bovine filarial parasite, by different effectors and its interaction with some antifilarials

<p>Abstract</p> <p>Background</p> <p>Phosphofructokinase (ATP: D-fructose-6-phosphate-1-phosphotransferase, EC 2.7.1.11, PFK) is of primary importance in the regulation of glycolytic flux. This enzyme has been extensively studied from mammalian sources but relatively less attention has been paid towards its characterization from filarial parasites. Furthermore, the information about the response of filarial PFK towards the anthelmintics/antifilarial compounds is lacking. In view of these facts, PFK from <it>Setaria cervi</it>, a bovine filarial parasite having similarity with that of human filarial worms, was isolated, purified and characterized.</p> <p>Results</p> <p>The <it>S. cervi </it>PFK was cytosolic in nature. The adult parasites (both female and male) contained more enzyme activity than the microfilarial (Mf) stage of <it>S. cervi</it>, which exhibited only 20% of total activity. The <it>S. cervi </it>PFK could be modulated by different nucleotides and the response of enzyme to these nucleotides was dependent on the concentrations of substrates (F-6-P and ATP). The enzyme possessed wide specificity towards utilization of the nucleotides as phosphate group donors. <it>S. cervi </it>PFK showed the presence of thiol group(s) at the active site of the enzyme, which could be protected from inhibitory action of para-chloromercuribenzoate (p-CMB) up to about 76% by pretreatment with cysteine or β-ME. The sensitivity of PFK from <it>S. cervi </it>towards antifilarials/anthelmintics was comparatively higher than that of mammalian PFK. With suramin, the Ki value for rat liver PFK was 40 times higher than PFK from <it>S. cervi</it>.</p> <p>Conclusions</p> <p>The results indicate that the activity of filarial PFK may be modified by different effectors (such as nucleotides, thiol group reactants and anthelmintics) in filarial worms depending on the presence of varying concentrations of substrates (F-6-P and ATP) in the cellular milieu. It may possess thiol group at its active site responsible for catalysis. Relatively, 40 times higher sensitivity of filarial PFK towards suramin as compared to the analogous enzyme from the mammalian system indicates that this enzyme could be exploited as a potential chemotherapeutic target against filariasis.</p

The Formation and Evolution of the First Massive Black Holes

The first massive astrophysical black holes likely formed at high redshifts (z>10) at the centers of low mass (~10^6 Msun) dark matter concentrations. These black holes grow by mergers and gas accretion, evolve into the population of bright quasars observed at lower redshifts, and eventually leave the supermassive black hole remnants that are ubiquitous at the centers of galaxies in the nearby universe. The astrophysical processes responsible for the formation of the earliest seed black holes are poorly understood. The purpose of this review is threefold: (1) to describe theoretical expectations for the formation and growth of the earliest black holes within the general paradigm of hierarchical cold dark matter cosmologies, (2) to summarize several relevant recent observations that have implications for the formation of the earliest black holes, and (3) to look into the future and assess the power of forthcoming observations to probe the physics of the first active galactic nuclei.Comment: 39 pages, review for "Supermassive Black Holes in the Distant Universe", Ed. A. J. Barger, Kluwer Academic Publisher

Low-Weight Primes for Lightweight Elliptic Curve Cryptography on 8-bit AVR Processors

Small 8-bit RISC processors and micro-controllers based on the AVR instruction set architecture are widely used in the embedded domain with applications ranging from smartcards over control systems to wireless sensor nodes. Many of these applications require asymmetric encryption or authentication, which has spurred a body of research into implementation aspects of Elliptic Curve Cryptography (ECC) on the AVR platform. In this paper, we study the suitability of a special class of finite fields, the so-called Optimal Prime Fields (OPFs), for a "lightweight" implementation of ECC with a view towards high performance and security. An OPF is a finite field Fp defined by a prime of the form p = u*2^k + v, whereby both u and v are "small" (in relation to 2^k) so that they fit into one or two registers of an AVR processor. OPFs have a low Hamming weight, which allows for a very efficient implementation of the modular reduction since only the non-zero words of p need to be processed. We describe a special variant of Montgomery multiplication for OPFs that does not execute any input-dependent conditional statements (e.g. branch instructions) and is, hence, resistant against certain side-channel attacks. When executed on an Atmel ATmega processor, a multiplication in a 160-bit OPF takes just 3237 cycles, which compares favorably with other implementations of 160-bit modular multiplication on an 8-bit processor. We also describe a performance-optimized and a security-optimized implementation of elliptic curve scalar multiplication over OPFs. The former uses a GLV curve and executes in 4.19M cycles (over a 160-bit OPF), while the latter is based on a Montgomery curve and has an execution time of approximately 5.93M cycles. Both results improve the state-of-the-art in lightweight ECC on 8-bit processors