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The tight junction protein claudin-3 has been identified as a transcriptional target of the Wnt/β-catenin signaling pathway regulating blood-brain barrier (BBB) maturation. In neurological disorders loss of claudin-3 immunostaining is observed at the compromised BBB and blood-cerebrospinal fluid barrier (BCSFB). Although these observations support a central role of claudin-3 in regulating brain barriers’ tight junction integrity, expression of claudin-3 at the brain barriers has remained a matter of debate. This prompted us to establish claudin-3 −/− C57BL/6J mice to study the role of claudin-3 in brain barrier integrity in health and neuroinflammation. Bulk and single cell RNA sequencing and direct comparative qRT-PCR analysis of brain microvascular samples from WT and claudin-3 −/− mice show beyond doubt that brain endothelial cells do not express claudin-3 mRNA. Detection of claudin-3 protein at the BBB in vivo and in vitro is rather due to junctional reactivity of anti-claudin-3 antibodies to an unknown antigen still detected in claudin-3 −/− brain endothelium. We confirm expression and junctional localization of claudin-3 at the BCSFB of the choroid plexus. Our study clarifies that claudin-3 is not expressed at the BBB and shows that absence of claudin-3 does not impair brain barrier function during health and neuroinflammation in C57BL/6J mice.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Female mosquitoes are major vectors of human disease and the most dangerous are those that preferentially bite humans. A ‘domestic’ form of the mosquito Aedes aegypti has evolved to specialize in biting humans and is the main worldwide vector of dengue, yellow fever, and chikungunya viruses. The domestic form coexists with an ancestral, ‘forest’ form that prefers to bite non-human animals and is found along the coast of Kenya. We collected the two forms, established laboratory colonies, and document striking divergence in preference for human versus non-human animal odour. We further show that the evolution of preference for human odour in domestic mosquitoes is tightly linked to increases in the expression and ligand-sensitivity of the odorant receptor AaegOr4 , which we found recognizes a compound present at high levels in human odour. Our results provide a rare example of a gene contributing to behavioural evolution and provide insight into how disease-vectoring mosquitoes came to specialize on humans. The mosquito Aedes aegypti includes two subspecies, one of which shows a preference for biting humans, whereas the other prefers to bite non-human animals; genetic analysis reveals that changes in the mosquito odorant receptor Or4 contribute to the behavioural difference—in human-preferring mosquitoes, Or4 is more highly expressed and more sensitive to sulcatone, a compound present at high levels in human odour. How mosquitoes got a taste for human blood A 'domestic' form of the mosquito Aedes aegypti , which is the major worldwide vector of dengue, yellow fever and chikungya viruses, has evolved from an ancestral 'forest' form. The former preferentially bites humans, the latter avoids them. Leslie Vosshall and colleagues collected the two forms where they coexist in coastal Kenya, and document striking divergence in preference for human versus animal odour. The human-preferring mosquito carries a version of the olfactory receptor Or4 that is more highly expressed, with greater ligand sensitivity and that makes the mosquito more sensitive to sulcatone, a compound found at high concentration in human odour. This finding provides a rare example of a gene linked to the evolution of behaviour in natural populations.

The Australian bearded dragon is so called for its distinctive ‘beard’ of spiky scales that can darken and expand during social and defensive displays. This lizard has become a reptilian model system to study the evolution, function and dynamics of neurons and neural circuits (including during sleep) in the amniote brain.

The liver has an intrinsic capacity to regenerate in response to injury or surgical resection. Nevertheless, circumstances in which hepatocytes are unresponsive to proliferative signals result in impaired regeneration and hepatic failure. As the Hippo pathway has a canonical role in the maintenance of liver size, we investigated whether it could serve as a therapeutic target to support regeneration. Using a standard two‐thirds partial hepatectomy (PH) model in young and aged mice, we demonstrate that the Hippo pathway is modulated across the phases of liver regeneration. The activity of the core kinases MST1 and LATS1 increased during the early hypertrophic phase and returned to steady state levels in the proliferative phase, coinciding with activation of YAP1 target genes and hepatocyte proliferation. Moreover, following PH in aged mice, we demonstrate that Hippo signaling is anomalous in non‐regenerating livers. We provide pre‐clinical evidence that silencing the Hippo core kinases MST1 and MST2 with siRNA provokes hepatocyte proliferation in quiescent livers and rescues liver regeneration in aged mice following PH. Our data suggest that targeting the Hippo core kinases MST1/2 has therapeutic potential to improve regeneration in non‐regenerative disorders. Synopsis Inhibition of the Hippo core kinases MST1 and MST2 with siRNA has the therapeutic potential to improve liver regeneration in age‐related non‐regenerative disorders. Hippo pathway proteins are differentially modulated throughout the quiescent, hypertrophic and proliferative phases of liver regeneration. In aged mice, the modulation of Hippo proteins following partial hepatectomy is altered and liver regeneration is impaired. siRNA encapsulated into liposomes efficiently targets liver parenchymal cells. Deletion of the Hippo core kinases MST1 and MST2 partially restores liver regeneration in a non‐regenerative aged mouse model, suggesting them as promising candidates as pharmacological targets to treat non‐regenerative disorders. Graphical Abstract Inhibition of the Hippo core kinases MST1 and MST2 with siRNA has the therapeutic potential to improve liver regeneration in age‐related non‐regenerative disorders.

Sex chromosomes are classically predicted to stop recombining in the heterogametic sex, thereby enforcing linkage between sex-determining (SD) and sex-antagonistic (SA) genes. With the same rationale, a pre-existing sex asymmetry in recombination is expected to affect the evolution of heterogamety, for example, a low rate of male recombination might favor transitions to XY systems, by generating immediate linkage between SD and SA genes. Furthermore, the accumulation of deleterious mutations on nonrecombining Y chromosomes should favor XY-to-XY transitions (which discard the decayed Y), but disfavor XY-to-ZW transitions (which fix the decayed Y as an autosome). Like many anuran amphibians, Hyla tree frogs have been shown to display drastic heterochiasmy (males only recombine at chromosome tips) and are typically XY, which seems to fit the above expectations. Instead, here we demonstrate that two species, H. sarda and H. savignyi, share a common ZW system since at least 11 Ma. Surprisingly, the typical pattern of restricted male recombination has been maintained since then, despite female heterogamety. Hence, sex chromosomes recombine freely in ZW females, not in ZZ males. This suggests that heterochiasmy does not constrain heterogamety (and vice versa), and that the role of SA genes in the evolution of sex chromosomes might have been overemphasized.

Animals on islands often exhibit dramatic differences in morphology and behaviour compared with mainland individuals, a phenomenon known as the ‘island syndrome’. These differences are thought to be adaptations to island environments, but the extent to which they have a genetic basis or instead represent plastic responses to environmental extremes is often unknown. Here, we revisit a classic case of island syndrome in deer mice (Peromyscus maniculatus) from British Columbia. We first show that Saturna Island mice and those from neighbouring islands are approximately 35% (approx. 5 g) heavier than mainland mice and diverged approximately 10 000 years ago. We then establish laboratory colonies and find that Saturna Island mice are heavier both because they are longer and have disproportionately more lean mass. These trait differences are maintained in second-generation captive-born mice raised in a common environment. In addition, island–mainland hybrids reveal a maternal genetic effect on body weight. Using behavioural testing in the laboratory, we also find that wild-caught island mice are less aggressive than mainland mice; however, laboratory-raised mice born to these founders do not differ in aggression. Together, our results reveal that these mice have different responses to the environmental conditions on islands—a heritable change in a morphological trait and a plastic response in a behavioural trait.

ObjectiveEvidence suggests interventions targeting low-acuity attendances have been hampered by insufficient characterisation of potential target groups. This study aimed to estimate the frequency of low-acuity emergency department (ED) attendances and to provide an overview of their demographic, diagnosis and consultation patterns.DesignObservational analyses of routine healthcare data.SettingGerman EDs.ParticipantsAdult patients with statutory health insurance who visited the ED of 16 participating hospitals in 2016.Main outcome measuresFrequency, demographics, diagnoses and consultation patterns of low-acuity and high-acuity attendees.Main resultsOf the 454 747 ED visits, 370 756 visits (50.1% female) were included for analysis. Four participating hospitals had to be excluded due to the lack of data that were necessary for the stepwise approach to define low and high acuity. We identified 101 337 visits as low acuity (27.3%) and 256 876 as high acuity (69.3%), whereas 12 543 (3.4%) could not be classified. The proportion of attendees classified as low acuity decreased with age (highest at 40.6% in the age group <35 years). The proportion of women and men was 50% in both acuity categories, respectively (50 654 of all low-acuity and 128 427 of all high-acuity contacts). The highest proportion of low-acuity presentations was observed during the weekend (average of 18.6% per day), compared with an average of 12.5% on weekdays. The most common diagnoses (back pain, abdominal and pelvic pain) were similar in both low-acuity and high-acuity groups.ConclusionOur study provides further evidence that younger age is associated with low-acuity presentation in German EDs. Age-specific intervention strategies are needed to ease the burden on urgent care facilities. The similar spectrum of diagnoses between low-acuity and high-acuity patients suggests a so far under-recognised higher importance of severity.Trial registration numberDRKS00022969.

Animals on islands often exhibit dramatic differences in morphology and behaviour compared with mainland individuals, a phenomenon known as the ‘island syndrome’. These differences are thought to be adaptations to island environments, but the extent to which they have a genetic basis or instead represent plastic responses to environmental extremes is often unknown. Here, we revisit a classic case of island syndrome in deer mice ( Peromyscus maniculatus ) from British Columbia. We first show that Saturna Island mice and those from neighbouring islands are approximately 35% (approx. 5 g) heavier than mainland mice and diverged approximately 10 000 years ago. We then establish laboratory colonies and find that Saturna Island mice are heavier both because they are longer and have disproportionately more lean mass. These trait differences are maintained in second-generation captive-born mice raised in a common environment. In addition, island–mainland hybrids reveal a maternal genetic effect on body weight. Using behavioural testing in the laboratory, we also find that wild-caught island mice are less aggressive than mainland mice; however, laboratory-raised mice born to these founders do not differ in aggression. Together, our results reveal that these mice have different responses to the environmental conditions on islands—a heritable change in a morphological trait and a plastic response in a behavioural trait.