T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma

In chronic viral hepatitis and in hepatocarcinoma (HCC), antigen-specific T cells are deeply exhausted, and evidence of dysfunction has also been observed for NK cells, which can play a pathogenetic role, exerting a regulatory activity on adaptive immune responses [...]

Revisiting regulatory decoherence: Accounting for temporal bias in a co-expression analysis reveals novel candidates controlling environmental response

Transcriptional Regulatory Networks (TRNs) orchestrate the timing, magnitude, and rate of organismal response to many environmental perturbations. Regulatory interactions in TRNs are dynamic but exploiting temporal variation to understand gene regulation requires a careful appreciation of both molecular biology and confounders in statistical analysis. Seeking to exploit the abundance of RNASequencing data now available, many past studies have relied upon population-level statistics from cross-sectional studies, estimating gene co-expression interactions to capture transient changes of regulatory activity. We show that population-level co-expression exhibits biases when capturing transient changes of regulatory activity in rice plants responding to elevated temperature. An apparent cause of this bias is regulatory saturation, the observation that detectable co-variance between a regulator and its target may be low as their transcript abundances are induced. This phenomenon appears to be particularly acute for rapid onset environmental stressors. However, exploiting temporal correlations appears to be a reliable means to detect transient regulatory activity following rapid onset environmental perturbations such as temperature stress. Such temporal correlation may lose information along a more gradual-onset stressor (e.g., dehydration). We here show that rice plants exposed to a dehydration stress exhibit temporal structure of coexpression in their response that can not be unveiled by temporal correlation alone. Collectively, our results point to the need to account for the nuances of molecular interactions and the possibly confounding effects that these can introduce into conventional approaches to study transcriptome datasets.

Decentralisation of Energy Generation, Centralisation of Energy Lawmaking

The energy sector has been subject to regulation since ancient times. The mechanisms of regulatory activity in this sector run like a red thread through history. New regulations are often born out of necessity (for example because of limited energy resources or today because of climate objectives). Switzerland’s energy law was originally a cantonal matter. Over the course of time, more and more competences have been transferred to the federal level. This, together with the increasing complexity of the subject matter of regulation, has led to a conflicting legal framework that renders it nearly impossible, even for experts, to answer everyday questions of competence with the necessary clarity and without much effort.

Wing Hearts in Four-Winged Ultrabithorax-mutant Flies—the role of Hox genes in wing heart specification

Wings are probably the most advanced evolutionary novelty in insects. The development of wings requires the activity of so-called wing hearts located in the scutellum of the thorax. Immediately after the imaginal ecdysis, these accessory circulatory organs remove haemolymph and apoptotic epidermal cells from the premature wing through their pumping action. This clearing process is essential for the formation of functional wing blades. Mutant Drosophila that lack intact wing hearts are flightless and display malformed wings. The embryonic wing heart progenitors originate from two adjacent parasegments corresponding to the later thoracic segments T2 and T3. However, the adult dipterian fly harbors only one pair of wing hearts and also only one pair of wings located in thoracic segment T2. Here we show, that the specification of wing heart progenitors depends on the regulatory activity of the Hox gene Ultrabithorax. Furthermore, we analysed the development of four wing hearts in the famous four-winged Ultrabithorax (Ubx) mutant, which was first discovered by Ed Lewis in the 1970s. In these flies, the third thoracic segment (T3) is transformed into a second thoracic segment (HT2). This results in a second pair of wings instead of the club-shaped halteres normally formed by T3. We show that a second pair of wild-type wing hearts is formed in the four-winged fly and that all wing hearts originate from the wild-type progenitor cells.

Leveraging interindividual variability of regulatory activity refines genetic regulation of gene expression in schizophrenia

Schizophrenia is a polygenic psychiatric disorder with limited understanding about the mechanistic changes in gene expression regulation. To elucidate on this, we integrate interindividual variability of regulatory activity with gene expression and genotype data captured from the prefrontal cortex of 272 cases and controls. We show that regulatory element activity is structured into 10,936 and 10,376 cis-regulatory domains in cases and controls, respectively, which display distinct regulatory element coordination structures in both states. By studying the interplay among genetic variants, gene expression and cis-regulatory domains, we ascertain that changes in coordinated regulatory activity tag alterations in gene expression levels (p=8.62e-06, OR=1.60), unveil case-specific QTL effects, and identify regulatory machinery changes for genes affecting synaptic function and dendritic spine morphology in schizophrenia. Altogether, we show that accounting for coordinated regulatory activity provides a novel mechanistic approach to reduce the search space for unveiling genetically perturbed regulation of gene expression in schizophrenia.

The Regulatory Activity of Noncoding RNAs in ILCs

Innate lymphoid cells (ILCs) are innate lymphocytes playing essential functions in protection against microbial infections and participate in both homeostatic and pathological contexts, including tissue remodeling, cancer, and inflammatory disorders. A number of lineage-defining transcription factors concur to establish transcriptional networks which determine the identity and the activity of the distinct ILC subsets. However, the contribution of other regulatory molecules in controlling ILC development and function is also recently emerging. In this regard, noncoding RNA (ncRNAs) represent key elements of the complex regulatory network of ILC biology and host protection. ncRNAs mostly lack protein-coding potential, but they are endowed with a relevant regulatory activity in immune and nonimmune cells because of their ability to control chromatin structure, RNA stability, and/or protein synthesis. Herein, we summarize recent studies describing how distinct types of ncRNAs, mainly microRNAs, long ncRNAs, and circular RNAs, act in the context of ILC biology. In particular, we comment on how ncRNAs can exert key effects in ILCs by controlling gene expression in a cell- or state-specific manner and how this tunes distinct functional outputs in ILCs.

Characterization of Potentized (Homeopathic, Anthroposophical and Antihomotoxic) Medicines Registered and Notified In Brazil

Background: Potentized medicines include, according to the Brazilian legislation, homeopathic, anthroposophic, and antihomotoxic medicine and are regulated by the Brazilian Health Surveillance Agency (ANVISA). Aim: This study aims to analyze and describe a profile of potentized medicines manufactured in Brazil, either registered or notified. Methodology: Information was obtained by data analysis related to ANVISA’s electronic medicine registration system. Results: The results, obtained as of September 2012, showed that 106 potentized medicines were registered and 519 were notified. Among the registered medicines, 92.0% were combined and 100.0% of the notified were simple medicines. For registered medicines, there were equivalent manufacturing scales among them, whereas for notified medicines, there was a predominance of centesimal scales. Active pharmaceutical ingredients (API’s) of vegetal origin were the most commonly used for potentized medicine manufacturing processes; the oral route was the most common form of administration. Potentized medicines manufacturing units are more often located in southeast region of Brazil. In addition, homeopathic medicines prevail as registered or notified medicines, followed by anthroposophic medicines. Conclusions: The results of the study are expected to be useful as reference material for ANVISA to improve its regulatory activity as well the industry sector and other stakeholders.