A conformational switch controlling the toxicity of the prion protein

Prion infections cause conformational changes of the cellular prion protein (PrPC) and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond (‘H-latch’), altering the flexibility of the α2–α3 and β2–α2 loops of PrPC. Expression of a PrP2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrPR207A mutant unable to form the H-latch conferred resistance to prion infection. High-affinity ligands that prevented H-latch induction repressed prion-related neurodegeneration in organotypic cerebellar cultures. We then selected phage-displayed ligands binding wild-type PrPC, but not PrP2Cys. These binders depopulated H-latched conformers and conferred protection against prion toxicity. Finally, brain-specific expression of an antibody rationally designed to prevent H-latch formation prolonged the life of prion-infected mice despite unhampered prion propagation, confirming that the H-latch is an important reporter of prion neurotoxicity

Recent advancements in the breeding of sorghum crop: current status and future strategies for marker-assisted breeding

Sorghum is emerging as a model crop for functional genetics and genomics of tropical grasses with abundant uses, including food, feed, and fuel, among others. It is currently the fifth most significant primary cereal crop. Crops are subjected to various biotic and abiotic stresses, which negatively impact on agricultural production. Developing high-yielding, disease-resistant, and climate-resilient cultivars can be achieved through marker-assisted breeding. Such selection has considerably reduced the time to market new crop varieties adapted to challenging conditions. In the recent years, extensive knowledge was gained about genetic markers. We are providing an overview of current advances in sorghum breeding initiatives, with a special focus on early breeders who may not be familiar with DNA markers. Advancements in molecular plant breeding, genetics, genomics selection, and genome editing have contributed to a thorough understanding of DNA markers, provided various proofs of the genetic variety accessible in crop plants, and have substantially enhanced plant breeding technologies. Marker-assisted selection has accelerated and precised the plant breeding process, empowering plant breeders all around the world

Re A (A Child) and the United Kingdom Code of Practice for the Diagnosis and Confirmation of Death: Should a Secular Construct of Death Override Religious Values in a Pluralistic Society?

The determination of death by neurological criteria remains controversial scientifically, culturally, and legally, worldwide. In the United Kingdom, although the determination of death by neurological criteria is not legally codified, the Code of Practice of the Academy of Medical Royal Colleges is customarily used for neurological (brainstem) death determination and treatment withdrawal. Unlike some states in the US, however, there are no provisions under the law requiring accommodation of and respect for residents’ religious rights and commitments when secular conceptions of death based on medical codes and practices conflict with a traditional concept well-grounded in religious and cultural values and practices. In this article, we analyse the medical, ethical, and legal issues that were generated by the recent judgement of the High Court of England and Wales in Re: A (A Child) [2015] EWHC 443 (Fam). Mechanical ventilation was withdrawn in this case despite parental religious objection to a determination of death based on the code of practice. We outline contemporary evidence that has refuted the reliability of tests of brainstem function to ascertain the two conjunctive clinical criteria for the determination of death that are stipulated in the code of practice: irreversible loss of capacity for consciousness and somatic integration of bodily biological functions

Ginkgo biloba Responds to Herbivory by Activating Early Signaling and Direct Defenses

Background: Ginkgo biloba (Ginkgoaceae) is one of the most ancient living seed plants and is regarded as a living fossil. G. biloba has a broad spectrum of resistance or tolerance to many pathogens and herbivores because of the presence of toxic leaf compounds. Little is known about early and late events occurring in G. biloba upon herbivory. The aim of this study was to assess whether herbivory by the generalist Spodoptera littoralis was able to induce early signaling and direct defense in G. biloba by evaluating early and late responses. Methodology/Principal Findings: Early and late responses in mechanically wounded leaves and in leaves damaged by S. littoralis included plasma transmembrane potential (Vm) variations, time-course changes in both cytosolic calcium concentration ([Ca 2+]cyt) and H2O2 production, the regulation of genes correlated to terpenoid and flavonoid biosynthesis, the induction of direct defense compounds, and the release of volatile organic compounds (VOCs). The results show that G. biloba responded to hebivory with a significant Vm depolarization which was associated to significant increases in both [Ca 2+] cyt and H 2O 2. Several defense genes were regulated by herbivory, including those coding for ROS scavenging enzymes and the synthesis of terpenoids and flavonoids. Metabolomic analyses revealed the herbivore-induced production of several flavonoids and VOCs. Surprisingly, no significant induction by herbivory was found for two of the most characteristic G. biloba classes of bioactive compounds; ginkgolides and bilobalides

High plasma uric acid concentration: causes and consequences

High plasma uric acid (UA) is a precipitating factor for gout and renal calculi as well as a strong risk factor for Metabolic Syndrome and cardiovascular disease. The main causes for higher plasma UA are either lower excretion, higher synthesis or both. Higher waist circumference and the BMI are associated with higher insulin resistance and leptin production, and both reduce uric acid excretion. The synthesis of fatty acids (tryglicerides) in the liver is associated with the de novo synthesis of purine, accelerating UA production. The role played by diet on hyperuricemia has not yet been fully clarified, but high intake of fructose-rich industrialized food and high alcohol intake (particularly beer) seem to influence uricemia. It is not known whether UA would be a causal factor or an antioxidant protective response. Most authors do not consider the UA as a risk factor, but presenting antioxidant function. UA contributes to > 50% of the antioxidant capacity of the blood. There is still no consensus if UA is a protective or a risk factor, however, it seems that acute elevation is a protective factor, whereas chronic elevation a risk for disease

DIS3 isoforms vary in their endoribonuclease activity and are differentially expressed within haematological cancers

DIS3 is the catalytic subunit of the exosome, a protein complex involved in the 3’ to 5’ degradation of RNAs. DIS3 is a highly conserved exoribonuclease, also known as Rrp44. Global sequencing studies have identified DIS3 as being mutated in a range of cancers, with a considerable incidence in multiple myeloma. In this work, we have identified two proteincoding isoforms of DIS3. Both isoforms are functionally relevant and result from alternative splicing. They differ from each other in the size of their N-terminal PIN domain, which has been shown to have endoribonuclease activity and tether DIS3 to the exosome. Isoform 1 encodes a full-length PIN domain, whereas the PIN domain of isoform 2 is shorter and is missing a segment with conserved amino-acids. We have carried out biochemical activity assays on both isoforms of full-length DIS3 as well as the isolated PIN domains. We find that isoform 2, despite missing part of the PIN domain, has greater endonuclease activity compared to isoform 1. Examination of the available structural information allows us to provide a hypothesis to explain this altered behaviour. Our results also show that multiple myeloma patient cells and all cancer cell lines tested have higher levels of isoform 1 compared to isoform 2 whereas Acute Myeloid Leukemia (AML) and chronic myelomonocytic leukaemia (CMML) patient cells and samples from healthy donors have similar levels of isoforms 1 and 2. Together, our data indicate that significant changes in the ratios of the two isoforms could be symptomatic of haematological cancers