In the age of next-generation sequencing, the number of loci available for phylogenetic analyses has increased by orders of magnitude. But despite this dramatic increase in the amount of data, some phylogenomic studies have revealed rampant gene-tree discordance that can be caused by many historical processes, such as rapid diversification, gene duplication, or reticulate evolution. We used a target enrichment approach to sample 400 single-copy nuclear genes and estimate the phylogenetic relationships of 13 genera in the lichen-forming family Lobariaceae to address the effect of data type (nucleotides and amino acids) and phylogenetic reconstruction method (concatenation and species tree approaches). Furthermore, we examined datasets for evidence of historical processes, such as rapid diversification and reticulate evolution. We found incongruence associated with sequence data types (nucleotide vs. amino acid sequences) and with different methods of phylogenetic reconstruction (species tree vs. concatenation). The resulting phylogenetic trees provided evidence for rapid and reticulate evolution based on extremely short branches in the backbone of the phylogenies. The observed rapid and reticulate diversifications may explain conflicts among gene trees and the challenges to resolving evolutionary relationships. Based on divergence times, the diversification at the backbone occurred near the Cretaceous-Paleogene (K-Pg) boundary (65 Mya) which is consistent with other rapid diversifications in the tree of life. Although some phylogenetic relationships within the Lobariaceae family remain with low support, even with our powerful phylogenomic dataset of up to 376 genes, our use of target-capturing data allowed for the novel exploration of the mechanisms underlying phylogenetic and systematic incongruence.

Extracellular high-mobility group box-1 (HMGB1) acts as a signalling molecule during inflammation, cell differentiation and angiogenesis. Increased abundance of HMGB1 is associated with several pathological disorders such as cancer, asthma and chronic obstructive pulmonary disease (COPD). In this study, we investigated the relevance of HMGB1 in the pathological remodelling present in patients with idiopathic pulmonary arterial hypertension (IPAH) and pulmonary hypertension (PH) associated with COPD. Remodelled vessels present in COPD with PH and IPAH lung samples were often surrounded by HMGB1-positive cells. Increased HMGB1 serum levels were detected in both patient populations compared to control samples. The effects of physiological HMGB1 concentrations were then examined on cellular responses in vitro. HMGB1 enhanced proliferation of pulmonary arterial smooth muscle cells (PASMC) and primary human arterial endothelial cells (PAEC). HMGB1 stimulated p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) phosphorylation. Furthermore, activation of the downstream AP-1 complex proteins c-Fos and c-Jun was observed. Silencing of c-Jun ablated the HMGB1-induced proliferation in PASMC. Thus, an inflammatory component such as HMGB1 can contribute to PASMC and PAEC proliferation and therefore potentially to vascular remodelling and PH pathogenesis.

Cultivated flax (Linum usitatissimum L.) is the earliest oil and fiber crop and its early domestication history may involve multiple events of domestication for oil, fiber, capsular indehiscence, and winter hardiness. Genetic studies have demonstrated that winter cultivated flax is closely related to oil and fiber cultivated flax and shows little relatedness to its progenitor, pale flax (L. bienne Mill.), but winter hardiness is one major characteristic of pale flax. Here, we assessed the genetic relationships of 48 Linum samples representing pale flax and four trait-specific groups of cultivated flax (dehiscent, fiber, oil, and winter) through population-based resequencing at 24 genomic regions, and revealed a winter group of cultivated flax that displayed close relatedness to the pale flax samples. Overall, the cultivated flax showed a 27% reduction of nucleotide diversity when compared with the pale flax. Recombination frequently occurred at these sampled genomic regions, but the signal of selection and bottleneck was relatively weak. These findings provide some insight into the impact and processes of flax domestication and are significant for expanding our knowledge about early flax domestication, particularly for winter hardiness.

Understanding crops genetic diversity and the evolutionary processes that accompanied their worldwide spread is useful for designing effective breeding strategies. Madagascar Island was one of the last major Old World areas where human settlement brought the introduction of Oryza sativa. Early studies in the island had reported the presence of a rice group specific to Madagascar. Using 24 K SNP, we compared diversity patterns at the whole genome and at haplotype (30 SNP-long segments along the genome) levels, between 620 Malagasy and 1929 Asian rice accessions. The haplotype level analysis aimed at identifying local genotypic variations, relative to the whole genome level, using a group assignment method that relies on kernel density estimation in a Principal Component Analysis feature space. Migration bottleneck had resulted in 10-25% reduction of diversity among the Malagasy representatives of indica and japonica populations. Compared to their Asian counterpart, they showed slightly lower indica and japonica introgressions, suggesting the two populations had undergone less recombination when migration to the island occurred. The origins of the Malagasy indica and japonica groups were delineated to indica subpopulation from the Indian subcontinent and to tropical japonica from the Malay Archipelago, respectively. The Malagasy-specific group (Gm) had a rather high gene diversity and an original haplotype pattern: much lower share of indica haplotypes, and much higher share of Aus and japonica haplotypes than indica. Its emergence and expansion are most probably due to inter-group recombination facilitated by sympatry between indica-Aus admixes and "Bulu" type landraces of japonica in the central high plateaux of Madagascar, and to human selection for adaptation to the lowland rice cultivation. Pattern of rice genetic diversity was also tightly associated with the history of human settlement in the island. Emergence of the Gm group is associated with the latest arrivals of Austronesians, who founded the Merina kingdom in the high plateaux and developed lowland rice cultivation. As an intermediary form between Aus, indica and japonica, the three pillars of O. sativa domestication, Gm represents a very valuable genetic resource in breeding for adaptation to cold tolerance in tropical highlands. We proposed the name Rojo for this new rice group.

Rare diseases are an important public health issue with high unmet need. The introduction of the EU Regulation on orphan medicinal products (OMP) has been successful in stimulating investment in the research and development of OMPs. Despite this advancement, patients do not have universal access to these new medicines. There are many factors that affect OMP uptake, but one of the most important is the difficulty of making pricing and reimbursement (P&R) decisions in rare diseases. Until now, there has been little consensus on the most appropriate assessment criteria, perspective or appraisal process. This paper proposes nine principles to help improve the consistency of OMP P&R assessment in Europe and ensure that value assessment, pricing and funding processes reflect the specificities of rare diseases and contribute to both the sustainability of healthcare systems and the sustainability of innovation in this field. These recommendations are the output of the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL), a collaboration between rare disease experts, patient representatives, academics, health technology assessment (HTA) practitioners, politicians and industry representatives. ORPH-VAL reached its recommendations through careful consideration of existing OMP P&R literature and through a wide consultation with expert stakeholders, including payers, regulators and patients. The principles cover four areas: OMP decision criteria, OMP decision process, OMP sustainable funding systems and European co-ordination. This paper also presents a guide to the core elements of value relevant to OMPs that should be consistently considered in all OMP appraisals. The principles outlined in this paper may be helpful in drawing together an emerging consensus on this topic and identifying areas where consistency in payer approach could be achievable and beneficial. All stakeholders have an obligation to work together to ensure that the promise of OMP's is realised.

People often spontaneously engage in copying each other's postures and mannerisms, a phenomenon referred to as behavioral mimicry. Social psychology experiments indicate that mimicry denotes an implicit affiliative signal flexibly regulated in response to social requirements. Yet, the mediating processes and neural underpinnings of such regulation are largely unexplored. The present functional magnetic resonance imaging (fMRI) study examined mimicry regulation by combining an automatic imitation task with facial stimuli, varied on two social-affective dimensions: emotional expression (angry vs happy) and ethnic group membership (in- vs out-group). Behavioral data revealed increased mimicry when happy and when out-group faces were shown. Imaging results revealed that mimicry regulation in response to happy faces was associated with increased activation in the right temporo-parietal junction (TPJ), right dorsal premotor cortex (dPMC), and right superior parietal lobule (SPL). Mimicry regulation in response to out-group faces was related to increased activation in the left ventral premotor cortex (vPMC) and inferior parietal lobule (IPL), bilateral anterior insula, and mid-cingulate cortex (MCC). We suggest that mimicry in response to happy and to out-group faces is driven by distinct affiliative goals, and that mimicry regulation to attain these goals is mediated by distinct neuro-cognitive processes. Higher mimicry in response to happy faces seems to denote reciprocation of an affiliative signal. Higher mimicry in response to out-group faces, reflects an appeasement attempt towards an interaction partner perceived as threatening (an interpretation supported by implicit measures showing that out-group members are more strongly associated with threat). Our findings show that subtle social cues can result in the implicit regulation of mimicry. This regulation serves to achieve distinct affiliative goals, is mediated by different regulatory processes, and relies on distinct parts of an overarching network of task-related brain areas. Our findings shed new light on the neural mechanisms underlying the interplay between implicit action control and social cognition.

Although mucopolysaccharidoses (MPS), inherited metabolic diseases from the group of lysosomal storage diseases (LSD), are monogenic disorders, recent studies indicated that their molecular mechanisms are complicated. Storage of glycosaminoglycans (GAGs), arising from a deficiency in one of the enzymes involved in the degradation of these compounds, is the primary cause of each MPS type. However, dysfunctions of various cellular organelles and disturbance of cellular processes have been reported which contribute considerably to pathomechanisms of the disease. Here, we present a complex transcriptomic analysis in which all types and subtypes of MPS were investigated, with special emphasis on genes related to cell activation processes. Complex changes in expression of these genes were found in fibroblasts of all MPS types, with number of transcripts revealing higher or lower levels (relative to control fibroblasts) between 19 and over 50, depending on MPS type. Genes in which expression was significantly affected in most MPS types code for proteins involved in following processes, classified according to Gene Ontology knowledge database: cell activation, cell growth, cell recognition, and cell division. Levels of some transcripts (including CD9, CLU, MME and others) were especially significantly changed (over five times relative to controls). Our results are discussed in the light of molecular pathomechanisms of MPS, indicating that secondary and/or tertiary changes, relative to GAG storage, might significantly modulate cellular dysfunctions and contribute to molecular mechanisms of the disease. This may influence the efficacy of various therapies and suggests why various treatments are not fully effective in improving the complex symptoms of MPS.

Social group categorization has been mainly studied in relation to ownership manipulations involving highly-salient multisensory cues. Here, we propose a novel paradigm that can implicitly activate the embodiment process in the presence of group affiliation information, whilst participants complete a task irrelevant to social categorization. Ethnically White participants watched videos of White- and Black-skinned models writing a proverb. The writing was interrupted 7, 4 or 1 s before completion. Participants were tasked with estimating the residual duration following interruption. A video showing only hand kinematic traces acted as a control condition. Residual duration estimates for out-group and control videos were significantly lower than those for in-group videos only for the longest duration. Moreover, stronger implicit racial bias was negatively correlated to estimates of residual duration for out-group videos. The underestimation bias for the out-group condition might be mediated by implicit embodiment, affective and attentional processes, and finalized to a rapid out-group categorization.

The efficacy and noninferior of performing modified double-door laminoplasty (MDDL) (C4-C6 laminoplasty plus C3 laminectomy, alongside a dome-like resection of the inferior part of the C2 lamina and the superior part of the C7 lamina) in patients with multilevel cervical spondylotic myelopathy (MCSM) is equivocal. A randomized, controlled trial is warranted.

One of the challenging questions in modelling biological systems is to characterize the functional forms of the processes that control and orchestrate molecular and cellular phenotypes. Recently proposed methods for the analysis of metabolic pathways, for example, dynamic flux estimation, can only provide estimates of the underlying fluxes at discrete time points but fail to capture the complete temporal behaviour. To describe the dynamic variation of the fluxes, we additionally require the assumption of specific functional forms that can capture the temporal behaviour. However, it also remains unclear how to address the noise which might be present in experimentally measured metabolite concentrations.

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.

The study aimed to examine the neural mechanisms underlying implicit other-race face processing by the use of the masked and unmasked priming manipulation. Two types of prime-target pairs were presented while recording Event-related potentials (ERPs): Same face pairs (prime-target were identical faces), and Different face pairs (prime-target were different faces). Prime-target pairs were half Asian (other-race) and half Caucasian (own-race) faces. The face stimuli on each pair were of the same gender and race. Participants (all Caucasians) had to decide whether the target was a male or a female face (gender task). The prime face could be unmasked or masked. On the behavioral side, our findings showed a race effect, that is slower reaction times (RTs) for other-race than own-race face stimuli, regardless of masking. On the ERPs side, our data showed a race effect across all components analyzed (P100, N100, N200, P300), under both the unmasked and masked manipulations. Besides, we found, in the unmasked condition, a priming effect as a function of race on the N100, N200, and P300 components; but, interestingly, in the masked condition, only on the P300. Overall, our findings provide evidence that race information is available very early in the brain and can strongly activate and influence people's behaviors even without conscious awareness.

Humans everywhere cooperate in groups to achieve benefits not attainable by individuals. Individual effort is often not automatically tied to a proportionate share of group benefits. This decoupling allows for free-riding, a strategy that (absent countermeasures) outcompetes cooperation. Empirically and formally, punishment potentially solves the evolutionary puzzle of group cooperation. Nevertheless, standard analyses appear to show that punishment alone is insufficient, because second-order free riders (those who cooperate but do not punish) can be shown to outcompete punishers. Consequently, many have concluded that other processes, such as cultural or genetic group selection, are required. Here, we present a series of agent-based simulations that show that group cooperation sustained by punishment easily evolves by individual selection when you introduce into standard models more biologically plausible assumptions about the social ecology and psychology of ancestral humans. We relax three unrealistic assumptions of past models. First, past models assume all punishers must punish every act of free riding in their group. We instead allow punishment to be probabilistic, meaning punishers can evolve to only punish some free riders some of the time. This drastically lowers the cost of punishment as group size increases. Second, most models unrealistically do not allow punishment to recruit labor; punishment merely reduces the punished agent's fitness. We instead realistically allow punished free riders to cooperate in the future to avoid punishment. Third, past models usually restrict agents to interact in a single group their entire lives. We instead introduce realistic social ecologies in which agents participate in multiple, partially overlapping groups. Because of this, punitive tendencies are more expressed and therefore more exposed to natural selection. These three moves toward greater model realism reveal that punishment and cooperation easily evolve by direct selection--even in sizeable groups.

Nucleoredoxin (Nrx) is an oxidoreductase of the thioredoxin family of proteins. It was shown to act as a signal transducer in some pathways; however, so far, no comprehensive analysis of its regulated substrates and functions was available. Here, we used a combination of two different strategies to fill this gap. First, we analyzed the thiol-redox state of the proteome of SH-SY5Y neuroblastoma cells depleted of Nrx compared to control cells using a differential thiol-labeling technique and quantitative mass spectrometry. 171 proteins were identified with an altered redox state; 161 of these were more reduced in the absence of Nrx. This suggests functions of Nrx in the oxidation of protein thiols. Second, we utilized the active site mutant Cys208Ser of Nrx, which stabilizes a mixed disulfide intermediate with its substrates and therefore trapped interacting proteins from the mouse brain (identifying 1710 proteins) and neuronal cell culture extracts (identifying 609 proteins). Profiling of the affected biological processes and molecular functions in cells of neuronal origin suggests numerous functions of Nrx in the redox regulation of metabolic pathways, cellular morphology, and signal transduction. These results characterize Nrx as a cellular oxidase that itself may be oxidized by the formation of disulfide relays with peroxiredoxins.

It well-known that mental training improves skill performance. Here, we evaluated skill acquisition and consolidation after physical or motor imagery practice, by means of an arm pointing task requiring speed-accuracy trade-off. In the main experiment, we showed a significant enhancement of skill after both practices (72 training trials), with a better acquisition after physical practice. Interestingly, we found a positive impact of the passage of time (+ 6 h post training) on skill consolidation for the motor imagery training only, without any effect of sleep (+ 24 h post training) for none of the interventions. In a control experiment, we matched the gain in skill learning after physical training (new group) with that obtained after motor imagery training (main experiment) to evaluate skill consolidation after the same amount of learning. Skill performance in this control group deteriorated with the passage of time and sleep. In another control experiment, we increased the number of imagined trials (n = 100, new group) to compare the acquisition and consolidation processes of this group with that observed in the motor imagery group of the main experiment. We did not find significant differences between the two groups. These findings suggest that physical and motor imagery practice drive skill learning through different acquisition and consolidation processes.

Oscillations of different origin, period and amplitude play an important role in the regulation of cellular processes. Most widely studied is the circadian or approximately daily variation in gene expression activity. Timing of gene expression is controlled by internal molecular clock keeping steady periodic expression. In this study, we shift attention towards a broad range of periodically expressed genes involved in multiple cellular functions which may or may not be under direct control of the intrinsic circadian clock. Are all molecular functions represented in expressed genes at all times? Alternatively, are different molecular functions performed at different times? Is there a pattern of succession for molecular processes and functions throughout their daily activity period?

Shape-deforming processes (e.g., squashing, bending, twisting) can radically alter objects' shapes. After such a transformation, some features are due to the object's original form, while others are due to the transformation, yet it is challenging to separate the two. We tested whether observers can distinguish the causal origin of different features, teasing apart the characteristics of the original shape from those imposed by transformations, a process we call 'shape scission'. Using computer graphics, we created 8 unfamiliar objects and subjected each to 8 transformations (e.g., "twisted", "inflated", "melted"). One group of participants named transformations consistently. A second group arranged cards depicting the objects into classes according to either (i) the original shape or (ii) the type of transformation. They could do this almost perfectly, suggesting that they readily distinguish the causal origin of shape features. Another group used a digital painting interface to indicate which locations on the objects appeared transformed, with responses suggesting they can localise features caused by transformations. Finally, we parametrically varied the magnitude of the transformations, and asked another group to rate the degree of transformation. Ratings correlated strongly with transformation magnitude with a tendency to overestimate small magnitudes. Responses were predicted by both the magnitude and area affected by the transformation. Together, the findings suggest that observers can scission object shapes into original shape and transformation features and access the resulting representational layers at will.

Working memory (WM) entails maintenance and manipulation of information in the absence of sensory input. This study investigated the trajectories and neural basis of these component processes of WM functions in aging. Longitudinal human functional magnetic resonance imaging (fMRI) data are presented from 136 older individuals (55-80 years) who were scanned at baseline and again 4 years later. We obtained evidence that age-related changes in parietal and frontal components of the WM core network are dissociable in terms of their role in maintenance of perceptual representations and further manipulation of this information, respectively. Individual difference analyses in performance subgroups showed that only prefrontal changes in fMRI activation were accompanied by changes in performance, but parietal brain activity was related to study dropout. We discuss the results in terms of possible neurobiological causes underlying separable aging-related declines in inferior parietal cortex and lateral prefrontal cortex that differentially affect WM functions.

Intervertebral disc herniation (IVDH) is an important pathology in humans and also in dogs. While the molecular disease mechanisms are well investigated in humans, little is known about the inflammatory mediators in naturally occurring canine IVDH. The objective of this study was to investigate whether the involved proinflammatory cytokines in human IVDH are also key cytokines in canine IVDH and thus to elucidate the suitability of the dog as a model for human trials. 59 samples from 25 dogs with surgically confirmed thoracolumbar IVDH were collected and classified in three subgroups: herniated (H), affected non-herniated (NH) disc, and adjacent non-affected (NA) disc. Discs from 11 healthy dogs acted as controls (C). Samples were analyzed for IL-1, IL-6, IL-8, and TNF-α expression (qPCR/ELISA) as well as cell infiltration and activation of the MAP kinase pathways (immunohistochemistry). Gene and protein expression of all key cytokines could be detected in IVDH affected dogs. Canine IVDH was significantly associated with a higher gene expression of IL-6 (H > C, NH > C) and TNF-α (H > C, NH > C, NA > C) and a significant down-regulation of IL-1β (H < C). Dogs with spontaneous pain had significantly higher IL-6 mRNA compared to those with pain arising only upon palpation. An inter-donor comparison (H and HN relative to NA) revealed a significant increase of IL-6 gene expression (H > NA, NH > NA). IL-8 (H > C, NA > C) and TNF-α (NH > C) protein levels were significantly increased in diseased dogs while inversely, IL-6 protein levels were significantly higher in patients with better clinical outcome. Aside from resident IVD cells, mostly monocytes and macrophages were found in extruded material, with concomitant activation of extracellular signal-regulated kinase p38 in the majority of samples. Dogs with spontaneous IVDH might provide a useful model for human disc diseases. Although the expression of key cytokines found in human IVDH was also demonstrated in canine tissue, the inflammatory mechanisms accompanying canine IVDH diverges partially from humans, which will require further investigations in the future. In dogs, IL-6 seems to play an important pathological role and may represent a new potential therapeutic target for canine patients.

As a group of membrane-anchored proteins, the proteins containing a disintegrin and metalloprotease domain (ADAMs) control many biological processes, especially for male fertility. Mouse Adam21 was previously found to be specifically expressed in the somatic cells and germ cells of testes, but its functional role during spermatogenesis and male reproductive processes is still unknown.