The evolution of brain architectures for predictive coding and active inference

This article considers the evolution of brain architectures for predictive processing. We argue that brain mechanisms for predictive perception and action are not late evolutionary additions of advanced creatures like us. Rather, they emerged gradually from simpler predictive loops (e.g. autonomic and motor reflexes) that were a legacy from our earlier evolutionary ancestors—and were key to solving their fundamental problems of adaptive regulation. We characterize simpler-to-more-complex brains formally, in terms of generative models that include predictive loops of increasing hierarchical breadth and depth. These may start from a simple homeostatic motif and be elaborated during evolution in four main ways: these include the multimodal expansion of predictive control into an allostatic loop; its duplication to form multiple sensorimotor loops that expand an animal's behavioural repertoire; and the gradual endowment of generative models with hierarchical depth (to deal with aspects of the world that unfold at different spatial scales) and temporal depth (to select plans in a future-oriented manner). In turn, these elaborations underwrite the solution to biological regulation problems faced by increasingly sophisticated animals. Our proposal aligns neuroscientific theorising—about predictive processing—with evolutionary and comparative data on brain architectures in different animal species. This article is part of the theme issue ‘Systems neuroscience through the lens of evolutionary theory’.

Novel open reading frames in human accelerated regions and transposable elements reveal new leads to understand schizophrenia and bipolar disorder

Schizophrenia (SCZ) and bipolar disorder are debilitating neuropsychiatric disorders arising from a combination of environmental and genetic factors. Novel open reading frames (nORFs) are genomic loci that give rise to previously uncharacterized transcripts and protein products. In our previous work, we have shown that nORFs can be biologically regulated and that they may play a role in cancer and rare diseases. More importantly, we have shown that nORFs may emerge in accelerated regions of the genome giving rise to species-specific functions. We hypothesize that nORFs represent a potentially important group of biological factors that may contribute to SCZ and bipolar disorder pathophysiology. Human accelerated regions (HARs) are genomic features showing human-lineage-specific rapid evolution that may be involved in biological regulation and have additionally been found to associate with SCZ genes. Transposable elements (TEs) are another set of genomic features that have been shown to regulate gene expression. As with HARs, their relevance to SCZ has also been suggested. Here, nORFs are investigated in the context of HARs and TEs. This work shows that nORFs whose expression is disrupted in SCZ and bipolar disorder are in close proximity to HARs and TEs and that some of them are significantly associated with SCZ and bipolar disorder genomic hotspots. We also show that nORF encoded proteins can form structures and potentially constitute novel drug targets.

Proteomic Analysis of Tears and Conjunctival Cells Collected with Schirmer Strips Using timsTOF Pro: Preanalytical Considerations

This study aimed to investigate the human proteome profile of samples collected from whole (W) Schirmer strips (ScS) and their two parts—the bulb (B) and the rest of the strip (R)—with a comprehensive proteomic approach using a trapped ion mobility mass spectrometer, the timsTOF Pro. Eight ScS were collected from two healthy subjects at four different visits to be separated into three batches, i.e., 4W, 4B, and 4R. In total, 1582 proteins were identified in the W, B, and R batches. Among all identified proteins, binding proteins (43.4%) and those with catalytic activity (42.2%) constituted more than 80% of the molecular functions. The most represented biological processes were cellular processes (31.2%), metabolic processes (20.8%), and biological regulation (13.1%). Enzymes were the most represented protein class (41%), consisting mainly of hydrolases (47.5%), oxidoreductases (22.1%), and transferases (16.7%). The bulb (B), which is in contact with the conjunctiva, might collect both tear and cell proteins and therefore promote the identification of more proteins. Processing B and R separately before mass spectrometry (MS) analysis, combined with the high data acquisition speed and the addition of ion-mobility-based separation in the timsTOF Pro, can bring a new dimension to biomarker investigations of a limited sample such as tear fluid.

Establishment and Application of Ligation Reaction-Based Method for Quantifying MicroR-156b

Microribonucleic acids (miRNAs) play significant roles in the regulation of biological processes and in responses to biotic or abiotic environmental stresses. Therefore, it is necessary to quantitatively detect miRNAs to understand these complicated biological regulation mechanisms. This study established an ultrasensitive and highly specific method for the quantitative detection of miRNAs using simple operations on the ground of the ligation reaction of ribonucleotide-modified deoxyribonucleic acid (DNA) probes. This method avoids the complex design of conventional reverse transcription. In the developed assay, the target miRNA miR156b was able to directly hybridize the two ribonucleotide-modified DNA probes, and amplification with universal primers was achieved following the ligation reaction. As a result, the target miRNA could be sensitively measured even at a detection limit as low as 0.0001 amol, and differences of only a single base could be detected between miR156 family members. Moreover, the proposed quantitative method demonstrated satisfactory results for overexpression-based genetically modified (GM) soybean. Ligation-based quantitative polymerase chain reaction (PCR) therefore has potential in investigating the biological functions of miRNAs, as well as in supervising activities regarding GM products or organisms.

Melatonin, Clock Genes, and Mammalian Reproduction: What Is the Link?

Physiological processes and behaviors in many mammals are rhythmic. Recently there has been increasing interest in the role of circadian rhythmicity in the control of reproductive function. The circadian rhythm of the pineal hormone melatonin plays a role in synchronizing the reproductive responses of animals to environmental light conditions. There is some evidence that melatonin may have a role in the biological regulation of circadian rhythms and reproduction in humans. Moreover, circadian rhythms and clock genes appear to be involved in optimal reproductive performance. These rhythms are controlled by an endogenous molecular clock within the suprachiasmatic nucleus (SCN) in the hypothalamus, which is entrained by the light/dark cycle. The SCN synchronizes multiple subsidiary oscillators (clock genes) existing in various tissues throughout the body. The basis for maintaining the circadian rhythm is a molecular clock consisting of transcriptional/translational feedback loops. Circadian rhythms and clock genes appear to be involved in optimal reproductive performance. This mini review summarizes the current knowledge regarding the interrelationships between melatonin and the endogenous molecular clocks and their involvement in reproductive physiology (e.g., ovulation) and pathophysiology (e.g., polycystic ovarian syndrome).

Ligand-induced changes in dynamics mediate long-range allostery in the lac repressor

Allostery, broadly defined as a protein's functional response to distal perturbations, is fundamental to biological regulation. In classical models, allosteric ligand binding produces a defined set of structural changes in the protein, resulting in a different low-energy conformation. Proteins that undergo ligand-induced allostery with few observable structural changes therefore frustrate interpretations by classical models. Here we used hydrogen-deuterium exchange with mass spectrometry (HDX/MS) to map the allosteric effects in a paradigm ligand-responsive allosteric transcription factor, the lac repressor (LacI). X-ray crystal structures of the core domain of LacI bound to different small molecule ligands, or the DNA operator, show less than 1.5 Å difference in the protein all-atom root-mean-square-deviation (RMSD) between any two structures. Despite this high degree of similarity among static structures, our HDX/MS experiments reveal widespread and unexpected differences in the flexibility of secondary structures in the LacI core domain in each functional state. We propose a model in which ligand binding allosterically switches the functional response of the repressor by selectively changing the dynamics of particular secondary structure elements relative to each other, shifting the conformational ensemble of the protein between mutually incompatible DNA-bound and inducer-bound states. Our model also provides a mechanistic context for the altered functions of thousands of documented LacI mutants. Furthermore, our approach provides a platform for characterizing and engineering allosteric responses in proteins.

An Exploration of Non-Coding RNAs in Extracellular Vesicles Delivered by Swine Anterior Pituitary

Extracellular vesicles are lipid bilayer-delimited particles carrying proteins, lipids, and small RNAs. Previous studies have demonstrated that they had regulatory functions both physiologically and pathologically. However, information remains inadequate on extracellular vesicles from the anterior pituitary, a key endocrine organ in animals and humans. In this study, we separated and identified extracellular vesicles from the anterior pituitary of the Duroc swine model. Total RNA was extracted and RNA-seq was performed, followed by a comprehensive analysis of miRNAs, lncRNAs, and circRNAs. Resultantly, we obtained 416 miRNAs, 16,232 lncRNAs, and 495 circRNAs. Furthermore, GO and KEGG enrichment analysis showed that the ncRNAs in extracellular vesicles may participate in regulating intracellular signal transduction, cellular component organization or biogenesis, small molecule binding, and transferase activity. The cross-talk between them also suggested that they may play an important role in the signaling process and biological regulation. This is the first report of ncRNA data in the anterior pituitary extracellular vesicles from the duroc swine breed, which is a fundamental resource for exploring detailed functions of extracellular vesicles from the anterior pituitary.

Pan-Cancer Analyses of Pyroptosis With Functional Implications in Prognosis and Immunotherapy in Cancer

Background Programmed cell death is an active and orderly form of cell death regulated by intracellular genes, which plays an important role in the normal occurrence and development of the immune system, and pyroptosis has been found to be involved in the tumorigenesis and development. However, compressive analysis and biological regulation about pyroptosis genes are lack in cancers. Methods Using the data from the The Cancer Genome Atlas, we established a score level model to quantify the pyroptosis level of cancer. Multi-omics bioinformatical analyses was performed to detect pyroptosis-related molecular features and effect of pyroptosis on immunotherapy in cancer. Results In the present study, we performed a comprehensive analysis of pyroptosis and its regulator genes in cancers. Most pyroptosis genes were aberrantly expressed among different cancer types, which is contributed by the CAN frequency and differences of DNA methylation level in cancer. We established the modeling of the pyroptosis level and found that pyroptosis showed dual roles across cancers, while the pyroptosis levels were different in multiple and be significantly associated with clinical prognosis. The dual role of pyroptosis also affect the effects of immunotherapy in several cancers. Multiple pyroptosis genes showed close connections with drug sensitivity across cancers, and may be considered as therapy targets in cancer. Conclusions Our comprehensive analyses provide new insight into the functions of pyroptosis in the initiation, development, and progression and treatment across cancers, suggesting corresponding prognostic and therapeutic utility.

New Insights on the Role of Connexins and Gap Junctions Channels in Adipose Tissue and Obesity

Due to the inability to curb the excessive increase in the prevalence of obesity and overweight, it is necessary to comprehend in more detail the factors involved in the pathophysiology and to appreciate more clearly the biochemical and molecular mechanisms of obesity. Thus, understanding the biological regulation of adipose tissue is of fundamental relevance. Connexin, a protein that forms intercellular membrane channels of gap junctions and unopposed hemichannels, plays a key role in adipogenesis and in the maintenance of adipose tissue homeostasis. The expression and function of Connexin 43 (Cx43) during the different stages of the adipogenesis are differentially regulated. Moreover, it has been shown that cell–cell communication decreases dramatically upon differentiation into adipocytes. Furthermore, inhibition of Cx43 degradation or constitutive overexpression of Cx43 blocks adipocyte differentiation. In the first events of adipogenesis, the connexin is highly phosphorylated, which is likely associated with enhanced Gap Junction (GJ) communication. In an intermediate state of adipocyte differentiation, Cx43 phosphorylation decreases, as it is displaced from the membrane and degraded through the proteasome; thus, Cx43 total protein is reduced. Cx is involved in cardiac disease as well as in obesity-related cardiovascular diseases. Different studies suggest that obesity together with a high-fat diet are related to the production of remodeling factors associated with expression and distribution of Cx43 in the atrium.