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Research on basic emotions has expanded beyond the traditional six categories, identifying over 20 distinct emotional states. However, differentiating some emotions remained challenging due to partially overlapping facial expressions. Grief and sadness are two such emotions that are difficult to distinguish. This study investigated the behavioral and neural mechanisms of grief perception in the prefrontal cortex (PFC), comparing it with sadness . Participants categorized and rated emotional facial images in grief and sadness conditions on valence, arousal, and dominance scales. While participants perceiving emotional facial images prefrontal cortex (PFC) hemodynamic activities were measured using functional near-infrared spectroscopy (fNIRS). Explicit behavioral responses showed no significant differences, however implicit measures (reaction times) revealed distinctions between grief and sadness perception. Further fNIRS results indicated increased oxy-Hb in the right dorsolateral PFC for grief condition images compared to sadness condition images. Additionally, cultural differences were observed, with Asian participants showing higher oxy-Hb responses in the dorsal PFC for unpleasant facial stimuli in grief conditions. These findings support cultural variability in emotion perception and regulation. The combination of behavioral reaction time and neuroimaging data suggests distinct implicit perceptual and neural processing mechanisms for grief and sadness . This indicates separate automatic implicit mechanisms for these emotions.

Anaplastic thyroid cancer (ATC) is an extremely aggressive tumor associated with poor prognosis due to a lack of efficient therapies. In Japan, lenvatinib is the only drug approved for patients with ATC; however, its efficacy is limited. Therefore, novel therapeutic strategies are urgently required for patients with ATC. The present study aimed to identify compounds that enhance the antiproliferative effects of lenvatinib in ATC cells using a compound library. IRAK1/4 Inhibitor I was identified as a candidate compound. Combined treatment with lenvatinib and IRAK1/4 Inhibitor I showed synergistic antiproliferative effects via the induction of cell cycle arrest at G2/M phase in the ATC cell lines 8305C, HTC/C3, ACT‐1, and 8505C. Furthermore, IRAK1/4 Inhibitor I enhanced the inhibition of ERK phosphorylation by lenvatinib in 8305C, HTC/C3, and 8505C cells. In an HTC/C3 xenograft mouse model, tumor volume was lower in the combined IRAK1/4 Inhibitor I and lenvatinib group compared with that in the vehicle control, IRAK1/4 Inhibitor I, and lenvatinib groups. IRAK1/4 Inhibitor I was identified as a promising compound that enhances the antiproliferative and antitumor effects of lenvatinib in ATC. We screened for novel compounds that could enhance the antiproliferative effects of lenvatinib in anaplastic thyroid cancer (ATC), which is an extremely aggressive tumor with poor prognosis. We identified IRAK1/4 Inhibitor I as a candidate compound and examined its combined use with lenvatinib. In our HTC/C3 xenograft mouse model, tumor volume was significantly lower in the combined IRAK1/4 Inhibitor I and lenvatinib group compared with that in the control, IRAK1/4 Inhibitor I alone, and lenvatinib alone groups.

Coat color is often highly variable within and between animal taxa. Among hundreds of pigmentation-related genes, melanocortin-1 receptor ( MC1R ) plays key roles in regulating the synthesis of the dark eumelanin and the red–yellow pheomelanin. The six species of macaques that inhabit Sulawesi Island diverged rapidly from their common ancestor, M. nemestrina. Unlike most macaques, Sulawesi macaques commonly have a dark coat color, with divergence in shade and color pattern. To clarify the genetic and evolutionary basis for coat color in Sulawesi macaques, we investigated the MC1R sequences and functional properties, including basal cAMP production and α-MSH-induced activity in vitro. We found fixed non-synonymous substitutions in MC1R in each species. Furthermore, we found that six species-specific variants corresponded with variation in agonist-induced and basal activity of MC1R. Inconsistent with the dark coat color, four substitutions independently caused decreases in the basal activity of MC1R in M. hecki, M. nigra, M. tonkeana, and M. ochreata . Selective analysis suggested MC1R of M. nigra and M. nigrescens underwent purifying selection. Overall, our results suggest that fixed differences in MC1R resulted in different functional characteristics and might contribute to divergence in color among the six Sulawesi macaque species.

Bitter taste enables the detection of potentially harmful substances and is mediated by bitter taste receptors, TAS2Rs, in vertebrates. Few antagonists and inverse agonists of TAS2Rs have been identified, especially natural compounds. TAS2R16s in humans, apes and Old World monkeys (Catarrhini, Anthropoidea) recognize β-glucoside analogues as specific agonists. Here, we investigated responses of TAS2R16 to β-glucosides in non-anthropoid primates, namely lemurs (Lemuriformes, Strepsirrhini). Salicin acted as an agonist on lemur TAS2R16. Arbutin acted as an agonist in the ring-tailed lemur ( Lemur catta ) but as an inverse agonist in black lemur ( Eulemur macaco ) and black-and-white ruffed lemur ( Varecia variegata ). We identified a strepsirrhine-specific amino acid substitution responsible for the inverse agonism of arbutin. In a food preference test, salicin bitterness was inhibited by arbutin in the black lemur. Structural modelling revealed this locus was important for a rearrangement of the intracellular end of transmembrane helix 7 (TM7). Accordingly, arbutin is the first known natural inverse agonist of TAS2Rs, contributing to our understanding of receptor–ligand interactions and the molecular basis of the unique feeding habit diversification in lemurs. Furthermore, the identification of a causal point mutation suggests that TAS2R can acquire functional changes according to feeding habits and environmental conditions.

Imprinted genes are expressed from a single parental allele, with the other allele often silenced by DNA methylation (DNAme) established in the germline. While species-specific imprinted orthologues have been documented, the molecular mechanisms underlying the evolutionary switch from biallelic to imprinted expression are unknown. During mouse oogenesis, gametic differentially methylated regions (gDMRs) acquire DNAme in a transcription-guided manner. Here we show that oocyte transcription initiating in lineage-specific endogenous retroviruses (ERVs) is likely responsible for DNAme establishment at 4/6 mouse-specific and 17/110 human-specific imprinted gDMRs. The latter are divided into Catarrhini- or Hominoidea-specific gDMRs embedded within transcripts initiating in ERVs specific to these primate lineages. Strikingly, imprinting of the maternally methylated genes Impact and Slc38a4 was lost in the offspring of female mice harboring deletions of the relevant murine-specific ERVs upstream of these genes. Our work reveals an evolutionary mechanism whereby maternally silenced genes arise from biallelically expressed progenitors. Although many species-specific imprinted genes have been identified, how the evolutionary switch from biallelic to imprinted expression occurs is still unknown. Here authors find that lineage-specific ERVs active as oocyte promoters can induce de novo DNA methylation at gDMRs and imprinting.

Some elderly cancer patients, even with good Eastern Cooperative Oncology Group performance status (ECOG-PS), have poor survival outcomes and cannot tolerate standard therapy. Few studies have detailed the associations between the G8 screening tool, ECOG-PS, and overall survival (OS) in such patients. Cancer patients, aged 70 years or older, were assessed for G8 and classified into three groups according to their G8 score: <11 as the low score group, 11-14 as the intermediate score group, and >14 as the high score group. We retrospectively analyzed the association between G8 score and OS in all patients and for each ECOG-PS-categorized group. Out of 264 enrolled patients, most patients (87%) with solid tumor were categorized as TNM stage IV. ECOG-PS was 0 or 1 in 215 patients and ≥2 in 48; there was missing data for one patient. Among all patients, the low score group with a median OS of 7.7 months survived significantly less than both the high score group with a median OS of 25.6 months [Hazard ratio (HR) 3.48; 95% confidence interval (CI), 1.96-6.63; p < 0.0001] and the intermediate score group with a median of 15.6 months (HR 1.83; 95% CI, 1.28-2.65; p < 0.001). In the multivariate analysis, TNM stage and G8 score were independent prognostic factors for OS. When patients with an ECOG-PS of 0 or 1 were analyzed, patients with a lower G8 score showed significantly shorter OS than patients with a higher score when any two groups were compared. This novel classification of the G8 score contributes to prompt identification of patients with poor prognosis and improved the prognostic value of ECOG-PS. Using G8 with ECOG-PS may be helpful in deciding treatment for elderly patients with advanced cancer.

Phosphatidylinositol‐3 kinase (PI3K) inhibitor and histone deacetylase (HDAC) inhibitor have been developed as potential anticancer drugs. However, the cytotoxicity of PI3K inhibitor or HDAC inhibitor alone is relatively weak. We recently developed a novel HDAC/PI3K dual inhibitor FK‐A11 and confirmed its enhanced cytotoxicity when compared to that of PI3K inhibitor or HDAC inhibitor alone on several cancer cell lines. However, the in vivo antitumor activity of FK‐A11 was insufficient. We conducted high‐throughput RNA interfering screening and identified gene LPIN1 which enhances the cytotoxicity of FK‐A11. Downregulation of LPIN1 enhanced simultaneous inhibition of HDAC and PI3K by FK‐A11 and enhanced the cytotoxicity of FK‐A11. Propranolol, a beta‐adrenoreceptor which is also a LPIN1 inhibitor, enhanced the in vitro and in vivo cytotoxicity and antitumor effect of FK‐A11. These findings should help in the development of FK‐A11 as a novel HDAC/PI3K dual inhibitor. High throughput gene suppression screening identified LPIN1 gene as the potential target that enhances the cytotoxicity of novel HDAC/PI3K dual inhibitor, FK‐A11. Treatment with propranolol, which is the LPIN1 inhibitor, significantly enhanced the antitumor effect of FK‐A11 in vivo.

Abstract Egg-laying mammals (monotremes) are a sister clade of therians (placental mammals and marsupials) and a key clade to understand mammalian evolution. They are classified into platypus and echidna, which exhibit distinct ecological features such as habitats and diet. Chemosensory genes, which encode sensory receptors for taste and smell, are believed to adapt to the individual habitats and diet of each mammal. In this study, we focused on the molecular evolution of bitter taste receptors (TAS2Rs) in monotremes. The sense of bitter taste is important to detect potentially harmful substances. We comprehensively surveyed agonists of all TAS2Rs in platypus (Ornithorhynchus anatinus) and short-beaked echidna (Tachyglossus aculeatus) and compared their functions with orthologous TAS2Rs of marsupial and placental mammals (i.e., therians). As results, the agonist screening revealed that the deorphanized monotreme receptors were functionally diversified. Platypus TAS2Rs had broader receptive ranges of agonists than those of echidna TAS2Rs. While platypus consumes a variety of aquatic invertebrates, echidna mainly consumes subterranean social insects (ants and termites) as well as other invertebrates. This result indicates that receptive ranges of TAS2Rs could be associated with feeding habits in monotremes. Furthermore, some orthologous receptors in monotremes and therians responded to β-glucosides, which are feeding deterrents in plants and insects. These results suggest that the ability to detect β-glucosides and other substances might be shared and ancestral among mammals.

Theoretically, divergent selection on sensory systems can cause speciation through sensory drive. However, empirical evidence is rare and incomplete. Here we demonstrate sensory drive speciation within island populations of cichlid fish. We identify the ecological and molecular basis of divergent evolution in the cichlid visual system, demonstrate associated divergence in male colouration and female preferences, and show subsequent differentiation at neutral loci, indicating reproductive isolation. Evidence is replicated in several pairs of sympatric populations and species. Variation in the slope of the environmental gradients explains variation in the progress towards speciation: speciation occurs on all but the steepest gradients. This is the most complete demonstration so far of speciation through sensory drive without geographical isolation. Our results also provide a mechanistic explanation for the collapse of cichlid fish species diversity during the anthropogenic eutrophication of Lake Victoria. Speciation in colour: a textbook example of evolution in action The cichlid fish of African lakes are textbook examples of rapid speciation but the mechanisms involved remain elusive. Observations of the cichlids in Lake Victoria now demonstrate the ecological and molecular basis of divergent evolution of the visual system (seen as divergence of vision genes, male coloration and female preferences) leading to speciation by sensory drive through interacting natural and sexual selection. The sensory drive hypothesis predicts that divergent adaptation in sensory and signalling systems to different environments can cause premating isolation between populations. As well as providing clear evidence that speciation can occur through sensory drive without geographical isolation, this work provides a mechanistic explanation for the collapse of cichlid fish species diversity during the anthropogenic eutrophication of Lake Victoria. This paper identifies the ecological and molecular basis of divergent evolution in the visual system of Lake Victoria cichlid fishes, leading to speciation through sensory drive without geographical isolation.

Recent research has revealed considerable evolutionary diversity in umami-taste (amino acids and nucleotides) and sweet-taste receptor TAS1R genes across vertebrate species. To contribute to a growing understanding of how diet shapes taste evolution, we studied TAS1R genes in non-anthropoid primates with highly diverse diets, including members of the Strepsirrhini, comprised of Lorisiformes (lorises) and Lemuriformes (lemurs), as well as members of the Tarsiiformes (tarsiers). We employed a targeted capture (TC) approach specifically probing all the three mammalian TAS1R genes, i.e., TAS1R1 (for sensing umami), TAS1R2 (sweet) and TAS1R3 (required for forming a heterodimer), followed by short-read massive-parallel sequencing for three lorisiform, four lemuriform, and one tarsiiform species. Analyzing together with publicly available whole-genome assemblies (WGAs) of non-anthropoids, we found that TAS1R1 and TAS1R2 of some lorisiform species were disrupted. The relative evolutionary rates in introns and synonymous sites of all the three TAS1R genes, as well as non-genic genome regions, of lorisiforms were higher than those of lemuriforms, a finding consistent with the higher genome-wide mutation rate of the lorisiforms. We found a similar pattern in the amino acid sequences and nonsynonymous sites of the sweet receptor TAS1R2 in lorisiforms. Evolutionary rates of amino acid sequences and nonsynonymous sites in TAS1R1 and TAS1R3 of lorisiforms were as slow as those of lemuriforms. This suggests that functional constraint on sweet sensing has been relaxed in lorisiform primates since their common ancestor. These results shed a new light on understanding evolutionary diversification of umami and sweet sensing in a diverse group of mammals.