Discovery of a Novel Small Molecule Inhibitor Targeting the Frataxin/Ubiquitin Interaction via Structure-Based Virtual Screening and Bioassays

Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardiodegenerative disorder for which there are no proven effective treatments. FRDA is caused by decreased expression and/or function of the mitochondrial protein frataxin. Here, we report findings that frataxin is degraded via the ubiquitin-proteasomal pathway and that it is ubiquitinated at residue K147 in Calu-6 cells. A theoretical model of the frataxin-K147/Ub complex, constructed by combining bioinformatics interface predictions with information-driven docking, revealed a hitherto unnoticed, potential ubiquitin-binding domain in frataxin. Through structure-based virtual screening and cell-based assays, we discovered a novel small molecule (compound (+)-11) able to prevent frataxin ubiquitination and degradation. (+)-11 was synthesized and tested for specific binding to frataxin by an UF-LC/MS based ligand-binding assay. Follow-up scaffold-based searches resulted in the identification of a lead series with micromolar activity in disrupting the frataxin/Ub interaction. This study also suggests that frataxin could be a potential target for FRDA drug development

Angular momentum of zero-frequency gravitons

By following closely Weinberg's soft theorem, which captures the 1/omega pole contribution to the amplitude for soft graviton emissions (omega < Lambda on top of an arbitrary background hard process, we calculate the expectation value of the graviton's angular momentum operator for arbitrary collisions dressed with soft radiation. We find that the result becomes independent of the cutoff Lambda on the graviton's frequency, effectively localizing at omega = 0. In this way, our result captures the contribution to the angular momentum that comes from the zero-frequency modes. Like the soft theorem, our formula has an exact dependence on the kinematics of the hard particles and is only a function of their momenta. As an example, we discuss in some detail the case of the 2 -> 2 scattering of spinless particles in General Relativity and N = 8 supergravity

Palmitoylethanolamide is a disease-modifying agent in peripheral neuropathy : pain relief and neuroprotection share a PPAR-alpha-mediated mechanism

Peer reviewedPublisher PD

Our products are safe (don’t tell anyone!). Why don’t supermarkets advertise their private food safety standards?

Large retail chains have spent considerable resources to promote production protocols andtraceability across the supply chain, aiming at increasing food safety. Yet, the majority of consumers areunaware of these private food safety standards (PFSS) and retailers are not informing them. This behaviordenotes a pooling paradox: supermarkets spend a large amount of money for food safety and yet they forgetto inform consumers. The result is a pooling equilibrium where consumers cannot discriminate among highquality and low quality products and supermarkets give up the potential price premium. This paper providesan economic explanation for the paradox using a contract-theory model. We found that PFSSimplementation may be rational even if consumers have no willingness to pay for safety, because thestandard can be used as a tool to solve asymmetric information along the supply chain. Using the PFSS,supermarkets can achieve a separating equilibrium where opportunistic suppliers have no incentive to acceptthe contract.Even if consumers exhibit a limited (but strictly positive) willingness to pay for safety, advertisingmay be profit-reducing. If the expected price margin is high enough, supermarkets have incentive to supplyboth certified and uncertified products. In this case, we show that, if consumers perceive undifferentiatedproducts as “reasonably safe”, supermarkets may maximize profits by pooling the goods and selling them asundifferentiated. This result is not driven by advertising costs, as we derive it assuming free advertising.[...

Seismic rehabilitation of cultural heritage masonry buildings with unbonded fiber reinforced elastomeric isolators (U-FREIs) \u2013 A case of study

In order to assess the structural behavior and to evaluate the seismic vulnerability of masonry structuresof relevant historical and artistic significance, which is a widespread building type in Italy and in the world,an historical masonry church is analyzed under earthquake loading. Linear and non-linear analyses areperformed on the finite element models of the structure. From these analyses it is pointed out that thestructure does not behave elastically in its existing condition even when subjected to the frequent designearthquake (81% probability of being exceeded over 50 years). Two traditional rehabilitation methods arestudied: the placement of a rigid diaphragm which connects the top of the masonry walls only enclosingthe church entrance area and the placement of a rigid diaphragm which connects the tops of all masonrywalls. None of the traditional method is sufficient for the structure to survive basic design earthquake(10% probability of being exceeded over 50 years). Hence an advanced seismic retrofit solution usinginnovative carbon fiber reinforced elastomeric isolators is proposed. The proposed intervention consistsin the installation of six Unbonded Fiber-Reinforced Elastomeric Isolators (U-FREI) and six Flat SurfaceSliders (FSS) as passive protective devices besides the placement of a rigid diaphragm which connects thetops of all masonry walls. The process of installation of the devices is illustrated. The use of the proposedsolution leads to a remarkable enhancement of the seismic response capacities of the structure; indeeda general elastic response under the Basic Design Earthquake (BDE) is attained

The lncRNAs at X Chromosome Inactivation Center: Not Just a Matter of Sex Dosage Compensation

Non‐coding RNAs (ncRNAs) constitute the majority of the transcriptome, as the result of pervasive transcription of the mammalian genome. Different RNA species, such as lncRNAs, miRNAs, circRNA, mRNAs, engage in regulatory networks based on their reciprocal interactions, often in a competitive manner, in a way denominated “competing endogenous RNA (ceRNA) networks” (“ceRNET”): miRNAs and other ncRNAs modulate each other, since miRNAs can regulate the expression of lncRNAs, which in turn regulate miRNAs, titrating their availability and thus competing with the binding to other RNA targets. The unbalancing of any network component can derail the entire regulatory circuit acting as a driving force for human diseases, thus assigning “new” functions to “old” molecules. This is the case of XIST, the lncRNA characterized in the early 1990s and well known as the essential molecule for X chromosome inactivation in mammalian females, thus preventing an imbalance of X‐linked gene expression between females and males. Currently, literature concerning XIST biology is becoming dominated by miRNA associations and they are also gaining prominence for other lncRNAs produced by the X‐inactivation center. This review discusses the available literature to explore possible novel functions related to ceRNA activity of lncRNAs produced by the X‐inactivation center, beyond their role in dosage compensation, with prospective implications for emerging gender‐biased functions and pathological mechanisms

Radiation reaction from soft theorems

Radiation reaction (RR) terms at the third post-Minkowskian (3PM) order have recently been found to be instrumental in restoring smooth continuity between the non-relativistic, relativistic, and ultra-relativistic (including the massless) regimes. Here we propose a new and intriguing connection between RR and soft (bremsstrahlung) theorems which short-circuits the more involved conventional loop computations. Although first noticed in the context of the maximally supersymmetric theory, unitarity and analyticity arguments support the general validity of this 3PM-order connection that we apply, in particular, to Einstein's gravity and to its Jordan-Brans-Dicke extension. In the former case we find full agreement with a recent result by Damour obtained through a very different reasoning

Human MicroRNAs Interacting With SARS-CoV-2 RNA Sequences: Computational Analysis and Experimental Target Validation

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel RNA virus affecting humans, causing a form of acute pulmonary respiratory disorder named COVID-19, declared a pandemic by the World Health Organization. MicroRNAs (miRNA) play an emerging and important role in the interplay between viruses and host cells. Although the impact of host miRNAs on SARS-CoV-2 infection has been predicted, experimental data are still missing. This study started by a bioinformatics prediction of cellular miRNAs potentially targeting viral RNAs; then, a number of criteria also based on experimental evidence and virus biology were applied, giving rise to eight promising binding miRNAs. Their interaction with viral sequences was experimentally validated by transfecting luciferase-based reporter plasmids carrying viral target sequences or their inverted sequences into the lung A549 cell line. Transfection of the reporter plasmids resulted in a reduction of luciferase activity for five out of the eight potential binding sites, suggesting responsiveness to endogenously expressed miRNAs. Co-transfection of the reporter plasmids along with miRNA mimics led to a further and strong reduction of luciferase activity, validating the interaction between miR-219a-2-3p, miR-30c-5p, miR-378d, miR-29a-3p, miR-15b-5p, and viral sequences. miR-15b was also able to repress plasmid-driven Spike expression. Intriguingly, the viral target sequences are fully conserved in more recent variants such as United Kingdom variant B.1.1.7 and South Africa 501Y.V2. Overall, this study provides a first experimental evidence of the interaction between specific cellular miRNAs and SARS-CoV-2 sequences, thus contributing to understanding the molecular mechanisms underlying virus infection and pathogenesis to envisage innovative therapeutic interventions and diagnostic tools

Genetic divergence in the cave cricket Troglophilus neglectus (Orthoptera Rhaphidophoridae): mitochondrial and nuclear DNA data.

In this study we used sequence polymorphisms at one mitochondrial and one nuclear gene (Cytochrome Oxidase subunit I and Internal Transcribed Spacer 1, respectively) to assess the degree of genetic divergence among 21 populations of the cave cricket Troglophilus neglectus (Orthoptera, Rhaphidophoridae), a species whose currently known range extends from the Balkan Peninsula to Southern Bavaria. Nineteen populations were sampled in Northern Italy, Slovenia, Croatia and Bosnia and Herzegovina, while two populations came from Germany (Lower Saxony) and Czech Republic, thus well outside the species range. Molecular data revealed a high level of fragmentation, with most of the study populations bearing exclusive haplotypes, the sole exception being the German and Czech specimens, which carried haplotypes also occurring at Slovenian locations. Spatial distribution of genetic heterogeneity and pattern of genetic divergence argue in favor of a recent origin of the two Central European populations, possibly through man-mediated dispersal event(s). These populations being not considered, our data are in remarkable agreement with a previous study based on allozymes conducted on a subset of populations of the same species and, more generally, with what is known on the population genetics of peri-Mediterranean Rhaphidophorids