Function of snail shell hairs in anti-predator defense.

The function and evolutionary background of the hairs on the shells of terrestrial gastropods is largely unknown. Many hypotheses proposed by malacologists have never been proven, and the long-held hypothesis of mechanical stability in wet environments has been rejected by recent studies. It would therefore be worthwhile to reexamine other hypotheses regarding the adaptive significance of shell hairs. We investigated the defense function of shell hairs against a specialist predator, the snail-eating firefly, in the long-haired snail Moellendorffia diminuta. The firefly larvae, which hunt snails using abdominal suckers, were unable to attach to the shell because of the shell hairs but were able to attach to the shells that had lost their hairs. About half of the hairy snails successfully defended themselves by swinging their shells and dropping firefly larvae, but most of the snails without hair failed to defend. The hairs reduce the ability of the larva to attach to the shell and increase the effectiveness of the shell-swinging defense behavior in removing the larva from the shell. As shell hairs grow longer with shell development, they may confer an advantage based on the predator's growth stage. Our findings highlight the anti-predator defense role of shell hairs in land snails, introducing a hypothesis previously overlooked in the evolutionary context of hairy snails.

Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability.

Expansions of repeat DNA tracts cause >70 diseases, and ongoing expansions in brains exacerbate disease. During expansion mutations, single-stranded DNAs (ssDNAs) form slipped-DNAs. We find the ssDNA-binding complexes canonical replication protein A (RPA1, RPA2, and RPA3) and Alternative-RPA (RPA1, RPA3, and primate-specific RPA4) are upregulated in Huntington disease and spinocerebellar ataxia type 1 (SCA1) patient brains. Protein interactomes of RPA and Alt-RPA reveal unique and shared partners, including modifiers of CAG instability and disease presentation. RPA enhances in vitro melting, FAN1 excision, and repair of slipped-CAGs and protects against CAG expansions in human cells. RPA overexpression in SCA1 mouse brains ablates expansions, coincident with decreased ATXN1 aggregation, reduced brain DNA damage, improved neuron morphology, and rescued motor phenotypes. In contrast, Alt-RPA inhibits melting, FAN1 excision, and repair of slipped-CAGs and promotes CAG expansions. These findings suggest a functional interplay between the two RPAs where Alt-RPA may antagonistically offset RPA's suppression of disease-associated repeat expansions, which may extend to other DNA processes.

Polymorphism at the nestling stage and host-specific mimicry in an Australasian cuckoo-host arms race.

Decades of research have shown that the coevolutionary arms race between avian brood parasites and their hosts can promote phenotypic diversification in hosts and brood parasites. However, relatively little is known about the role of brood parasitism in promoting phenotypic diversification of nestlings. We review field data collected over four decades in Australia, New Caledonia and New Zealand to assess potential for coevolutionary interactions between the shining bronze-cuckoo (Chalcites lucidus) and its hosts, and how diversification at the nestling stage may be generating different subspecies. The shining bronze-cuckoo is a specialist parasite of a few hosts in the family Acanthizidae. It has diversified into subspecies, of which the nestlings closely mimic the respective host nestlings in each region. Additionally, some cuckoo subspecies have polymorphic nestlings. The Acanthizidae hosts have similar breeding and nesting habits and only moderately effective frontline defences against parasitism at cuckoo egg laying or at the egg stages. However, some hosts have developed highly effective defences at the nestling stage by recognising and ejecting cuckoo nestlings from the nest. As with the cuckoo nestlings, some hosts have polymorphic nestlings. The coevolutionary interactions in each region suggest different evolutionary stages of the arms race in which either the parasite or the host is currently in the lead. The presence of moderately effective defences at the egg laying and egg stages might explain why some hosts do not have defences at the nestling stage. The south-Pacific cuckoo - host systems are excellent models to explore the evolutionary mechanisms driving the diversification at the nestling stage in the coevolutionary arms race between avian brood parasites and their hosts.

Advancing genomic technologies and clinical awareness accelerates discovery of disease-associated tandem repeat sequences.

Expansions of gene-specific DNA tandem repeats (TRs), first described in 1991 as a disease-causing mutation in humans, are now known to cause >60 phenotypes, not just disease, and not only in humans. TRs are a common form of genetic variation with biological consequences, observed, so far, in humans, dogs, plants, oysters, and yeast. Repeat diseases show atypical clinical features, genetic anticipation, and multiple and partially penetrant phenotypes among family members. Discovery of disease-causing repeat expansion loci accelerated through technological advances in DNA sequencing and computational analyses. Between 2019 and 2021, 17 new disease-causing TR expansions were reported, totaling 63 TR loci (>69 diseases), with a likelihood of more discoveries, and in more organisms. Recent and historical lessons reveal that properly assessed clinical presentations, coupled with genetic and biological awareness, can guide discovery of disease-causing unstable TRs. We highlight critical but underrecognized aspects of TR mutations. Repeat motifs may not be present in current reference genomes but will be in forthcoming gapless long-read references. Repeat motif size can be a single nucleotide to kilobases/unit. At a given locus, repeat motif sequence purity can vary with consequence. Pathogenic repeats can be "insertions" within nonpathogenic TRs. Expansions, contractions, and somatic length variations of TRs can have clinical/biological consequences. TR instabilities occur in humans and other organisms. TRs can be epigenetically modified and/or chromosomal fragile sites. We discuss the expanding field of disease-associated TR instabilities, highlighting prospects, clinical and genetic clues, tools, and challenges for further discoveries of disease-causing TR instabilities and understanding their biological and pathological impacts-a vista that is about to expand.

Discrimination and ejection of eggs and nestlings by the fan-tailed gerygone from New Caledonia.

Nestling rejection is a rare type of host defense against brood parasitism compared with egg rejection. Theoretically, host defenses at both egg and nestling stages could be based on similar underlying discrimination mechanisms but, due to the rarity of nestling rejector hosts, few studies have actually tested this hypothesis. We investigated egg and nestling discrimination by the fan-tailed gerygone Gerygone flavolateralis, a host that seemingly accepts nonmimetic eggs of its parasite, the shining bronze-cuckoo Chalcites lucidus, but ejects mimetic parasite nestlings. We introduced artificial eggs or nestlings and foreign gerygone nestlings in gerygone nests and compared begging calls of parasite and host nestlings. We found that the gerygone ejected artificial eggs only if their size was smaller than the parasite or host eggs. Ejection of artificial nestlings did not depend on whether their color matched that of the brood. The frequency of ejection increased during the course of the breeding season mirroring the increase in ejection frequency of parasite nestlings by the host. Cross-fostered gerygone nestlings were frequently ejected when lacking natal down and when introduced in the nest before hatching of the foster brood, but only occasionally when they did not match the color of the foster brood. Begging calls differed significantly between parasite and host nestlings throughout the nestling period. Our results suggest that the fan-tailed gerygone accepts eggs within the size range of gerygone and cuckoo eggs and that nestling discrimination is based on auditory and visual cues other than skin color. This highlights the importance of using a combined approach to study discrimination mechanisms of hosts.

Erratum to: Discrimination and ejection of eggs and nestlings by the fan-tailed gerygone from New Caledonia.

[This corrects the article DOI: 10.1093/cz/zoab066.].

Oculo-dento-digital Dysplasia Presenting as Spastic Paraparesis Which Was Successfully Treated by Intrathecal Baclofen Therapy.

A 42-year-old man with a history of migraine and bilateral syndactyly presented with numbness of the extremities and shaking legs, which thus prevented him from working as a carpenter. A neurological examination revealed spastic paraparesis with pathological reflexes on all four extremities. Oculo-dento-digital dysplasia (ODDD) was suspected based on his medical history and characteristic facial appearance including small eye slits, thin mouth, and pinched nose with anteverted nostrils. Genetic tests revealed a gap junction alpha 1 (GJA1) gene mutation and confirmed the diagnosis of ODDD. His spastic paraparesis was resistant to oral antispastic medication, however, his symptoms successfully improved after the initiation of intrathecal baclofen therapy, which thus allowed him to return to work.

The NAD Kinase Slr0400 Functions as a Growth Repressor in Synechocystis sp. PCC 6803.

NADP+, the phosphorylated form of nicotinamide adenine dinucleotide (NAD), plays an essential role in many cellular processes. NAD kinase (NADK), which is conserved in all living organisms, catalyzes the phosphorylation of NAD+ to NADP+. However, the physiological role of phosphorylation of NAD+ to NADP+ in the cyanobacterium Synechocystis remains unclear. In this study, we report that slr0400, an NADK-encoding gene in Synechocystis, functions as a growth repressor under light-activated heterotrophic growth conditions and light and dark cycle conditions in the presence of glucose. We show, via characterization of NAD(P)(H) content and enzyme activity, that NAD+ accumulation in slr0400-deficient mutant results in the unsuppressed activity of glycolysis and tricarboxylic acid (TCA) cycle enzymes. In determining whether Slr0400 functions as a typical NADK, we found that constitutive expression of slr0400 in an Arabidopsis nadk2-mutant background complements the pale-green phenotype. Moreover, to determine the physiological background behind the growth advantage of mutants lacking slr04000, we investigated the photobleaching phenotype of slr0400-deficient mutant under high-light conditions. Photosynthetic analysis found in the slr0400-deficient mutant resulted from malfunctions in the Photosystem II (PSII) photosynthetic machinery. Overall, our results suggest that NADP(H)/NAD(H) maintenance by slr0400 plays a significant role in modulating glycolysis and the TCA cycle to repress the growth rate and maintain the photosynthetic capacity.

Genome-wide detection of tandem DNA repeats that are expanded in autism.

Tandem DNA repeats vary in the size and sequence of each unit (motif). When expanded, these tandem DNA repeats have been associated with more than 40 monogenic disorders1. Their involvement in disorders with complex genetics is largely unknown, as is the extent of their heterogeneity. Here we investigated the genome-wide characteristics of tandem repeats that had motifs with a length of 2-20 base pairs in 17,231 genomes of families containing individuals with autism spectrum disorder (ASD)2,3 and population control individuals4. We found extensive polymorphism in the size and sequence of motifs. Many of the tandem repeat loci that we detected correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated expansions of tandem repeats that were rare among population control individuals were significantly more prevalent among individuals with ASD than their siblings without ASD, particularly in exons and near splice junctions, and in genes related to the development of the nervous system and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in children with ASD compared with 20.7% in children without ASD, which suggests that tandem repeat expansions make a collective contribution to the risk of ASD of 2.6%. These rare tandem repeat expansions included previously undescribed ASD-linked expansions in DMPK and FXN, which are associated with neuromuscular conditions, and in previously unknown loci such as FGF14 and CACNB1. Rare tandem repeat expansions were associated with lower IQ and adaptive ability. Our results show that tandem DNA repeat expansions contribute strongly to the genetic aetiology and phenotypic complexity of ASD.

Prey-tracking behavior and prey preferences in a tree-climbing firefly.

Prey-tracking behavior is common in snail-killing predators, but in the family Lampyridae, this behavior has been validated in only a single species even though this Coleopteran family includes many specialist snail predators. The endemic firefly Pyrocoelia atripennis is a major snail-killing predator in the Yaeyama Islands of Japan, and the larvae often climb on the trees and grasses at night. This tree-climbing behavior is relevant to larval food choices and anti-predatory defenses of land snails. This study examined whether lampyrid larvae can track snail mucus trails and examined larval prey preferences using alternative choice experiments. In addition, predation trials were conducted to evaluate which snail species are potential prey. P. atripennis larvae significantly selected mucous trails over distilled water or control (no-trail) treatments. In addition, a semi-arboreal species was preferred over a ground-dwelling species. In predation trials, the larvae preyed on five out of 10 endemic snail species, all of which were semi-arboreal or arboreal species. Ground-dwelling Cyclophoridae and Aegista species have effective anti-predatory defenses consisting of an operculum or "foamy-lid" that fills the shell aperture. Whether the prey has a lid affects the predation success of lampyrid larvae, and larval tree-climbing behavior may be an adaptation used to search for semi-arboreal and arboreal land snails that lack defensive lids. Furthermore, snail mucus left on the plant stem may help the lampyrid larvae to locate their prey.

Ataxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42.

Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel CaV3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of CaV3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His CaV3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.

Prevalence and clinicoradiological features of spinocerebellar ataxia type 34 in a Japanese ataxia cohort.

INTRODUCTION: Spinocerebellar ataxia (SCA) type 34, a form of autosomal dominantly inherited ataxia, has recently been associated with mutations in the ELOVL4 gene. However, a genetic study of the prevalence of SCA34 in an ataxia cohort has never been reported. METHODS: We performed a mutation screening of ELOVL4 in a cohort of 153 undiagnosed index ataxia patients, selected after excluding for common SCA types, in a series of 506 Japanese index ataxia patients. RESULTS: Heterozygous mutation c.698C > T (p.T233M) was detected in an index patient with multisystem neurodegeneration including ataxia and erythrokeratodermia skin lesions, an archetypal skin phenotype in SCA34. The patient's father also presented with ataxia but not skin lesions. Although this mutation has been recently reported in a single English-Canadian patient, the present study confirms its cosegregation with the ataxia phenotype in the Japanese kindred. Brain magnetic resonance imaging (MRI) of the patient and his father revealed marked pontine and cerebellar atrophy as well as the hot cross bun sign, that is common in cerebellar type of multiple system atrophy and was also described in SCA34 patients harboring two other mutations: p.L168F and p.W246G. CONCLUSION: This represents the first genetic study of the prevalence of SCA34 in an ataxia cohort and demonstrates its low prevalence (0.2%) in ataxia patients. The broad SCA34 clinical spectrum suggests variable multisystem neurodegeneration. Clinicians should be aware of this rare disease entity, particularly if erythrokeratodermia or the hot cross bun sign in MRI are present in undiagnosed degenerative ataxia patients.

Visual discrimination of polymorphic nestlings in a cuckoo-host system.

Mimicry by avian brood parasites favours uniformity over variation within a breeding attempt as host defence against parasitism. In a cuckoo-host system from New Caledonia, the arms race resulted in both host (Gerygone flavolateralis) and parasite (Chalcites lucidus) having nestlings of two discrete skin colour phenotypes, bright and dark. In our study sites, host nestlings occurred in monomorphic and polymorphic broods, whereas cuckoo nestlings only occurred in the bright morph. Irrespective of their brood colour, host parents recognised and ejected parasite nestlings but never ejected their own. We investigated whether host parents visually recognised their own nestlings by using colour, luminance and pattern of multiple body regions. We found that the parasite mimicked multiple visual features of both host morphs and that the visual difference between host morphs was larger than the difference between the parasite and the mimicked host morph. Visual discrimination alone may result in higher chances of recognition errors in polymorphic than in monomorphic host broods. Host parents may rely on additional sensorial cues, not only visual, to assess nestling identity. Nestling polymorphism may be a trace of evolutionary past and may only have a marginal role in true-recognition of nestlings in the arms race in New Caledonia.

A diagnostic decision tree for adult cerebellar ataxia based on pontine magnetic resonance imaging.

Cerebellar ataxias (CAs) are heterogeneous conditions often require differential diagnosis. This study aimed to establish a diagnostic decision tree for differentiating CAs based on pontine MRI findings. Two-hundred and two consecutive ataxia patients were clinically classified into 4 groups: (1) spinocerebellar ataxia (SCA) with brainstem involvement (SCA-BSI), (2) Pure cerebellar SCA, (3) cerebellar dominant multiple system atrophy (MSA-c), and (4) Other CA. Signal intensity in pons was graded into 3 types: hot cross bun sign (HCBS), pontine midline linear T2-hyperintensity (PMH), or normal. The distance ratio of pontine base to tegmentum, named "BT-ratio", was measured. The presence of HCBS indicated either MSA-c with a specificity of 97.7%, or SCA2. When PMH was observed, a BT-ratio above 3.54 strongly indicated SCA-BSI, namely Machado-Joseph disease, SCA1, or dentatorubral-pallidoluysian atrophy, whereas a BT-ratio below 3.54 indicated MSA-c or SCA2. When the signal intensity was normal, a BT-ratio above 3.52 indicated SCA-BSI, whereas a BT-ratio below 3.52 suggested Pure cerebellar SCA or Other CA with pure cerebellar type. The decision tree was confirmed useful in a different 30 CA patients. We propose that differential diagnosis of CAs can be supported by combining pontine MRI signal intensity changes and BT-ratio.

Mating system and extra-pair paternity in the Fan-tailed Gerygone Gerygone flavolateralis in relation to parasitism by the Shining Bronze-cuckoo Chalcites lucidus.

Extra-pair copulation can increase genetic diversity and offspring fitness. However, it may also increase intra-nest variability in avian hosts of brood parasites, which can decrease the discrimination ability of host parents towards the parasite. In New Caledonia, the Fan-tailed Gerygone (Gerygone flavolateralis), which is parasitized by the Shining Bronze-cuckoo (Chalcites lucidus), has two nestling morphs, dark and bright, that can occur in monomorphic and polymorphic broods. Gerygone parents recognize and eject parasite nestlings from their nest, but the presence of polymorphic broods may increase the chances of recognition errors. Using 17 microsatellite markers, we investigated the mating system of the Fan-tailed Gerygone to understand the mechanisms underlying nestling polymorphism. We hypothesised that extra-pair copulations would lead to a higher proportion of polymorphic broods caused by higher genetic variability, thus creating a trade-off between genetic benefits and host defence reliability. Extra-pair paternity occurred in 6 of 36 broods, which resulted in 6 of 69 offspring sired by extra-pair males. Broods with and without mixed paternity were comparably often parasitized. Extra-pair paternity did not influence the proportions of bright, dark and polymorphic broods. Compared to bright siblings in polymorphic broods, dark nestlings tended to have lower heterozygosity, particularly in loci associated with skin coloration. The results also suggested that there is no obstacle for genetic exchange between individuals from forest and savannah, possibly due to dispersal of offspring. We conclude that the Fan-tailed Gerygone is a socially monogamous species with a low rate of extra-pair paternity compared to closely related species. Extra-pair paternity increased offspring genetic variability without measurable associated costs by brood parasitism. The results highlight the importance of studying host mating systems to assess the trade-offs between host defence and offspring fitness in co-evolutionary arms races.

Spinocerebellar Ataxia Type 31 with Blepharospasm.

A 58-year-old man consulted our hospital due to a 2-year history of dysarthria and a 1-month history of blepharospasm. In addition to the ataxic dysarthria and blepharospasm, a neurological examination demonstrated slight ataxia of the trunk and lower limbs. Brain MRI demonstrated atrophy of the upper portion of the cerebellar vermis. Gene analysis established a diagnosis of spinocerebellar ataxia type 31 (SCA31). Single photon emission computed tomography (SPECT) with the three-dimensional stereotaxic ROI template (3DSRT) software program demonstrated hyperperfusion in the lenticular nucleus and thalamus. Although the association between SCA31 and blepharospasm in our patient remains unclear, we considered that this combination might be more than coincidental.

Sequence configuration of spinocerebellar ataxia type 8 repeat expansions in a Japanese cohort of 797 ataxia subjects.

Spinocerebellar ataxia type 8 (SCA8), an autosomal dominant neurodegenerative disorder showing slowly progressive cerebellar ataxia, is caused by a tri-nucleotide CTG repeat expansion (CTGexp) in the SCA8 gene. As the CTGexp is not fully penetrant, the significance of screening CTGexp in ataxia subjects remains obscure. We tested SCA8 CTGexp in a cohort of 797 ataxia subjects, and if present, its sequence configuration was analyzed. CTGexp was found in 16 alleles from 14 individuals, 2 of which was homozygous for CTGexp. Nucleotide sequencing disclosed 3 types of CTGexp sequence configurations: uninterrupted CTGexp, tri-nucleotide CTA interruption and CCG interruption. The 2 individuals with homozygous expansions were both sporadic cases with clinical features compatible with SCA8, supporting gene dosage effect. Seven out of 14 CTGexp-positive subjects were also carriers of other SCA expansions [Machado-Joseph disease (n=1), SCA6 (n=3) and SCA31 (n=3)], whereas 7 others were not complicated with such major SCAs. Ages of onset in subjects with pure CTGexp tended to be earlier than those with interrupted CTGexp among the 7 subjects not complicated by major SCAs, suggesting that pure CTGexp have stronger pathogenic effect than interrupted CTGexps. The present study underscores importance of disclosing sequence configuration when testing SCA8.

Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31.

Microsatellite expansion disorders are pathologically characterized by RNA foci formation and repeat-associated non-AUG (RAN) translation. However, their underlying pathomechanisms and regulation of RAN translation remain unknown. We report that expression of expanded UGGAA (UGGAAexp) repeats, responsible for spinocerebellar ataxia type 31 (SCA31) in Drosophila, causes neurodegeneration accompanied by accumulation of UGGAAexp RNA foci and translation of repeat-associated pentapeptide repeat (PPR) proteins, consistent with observations in SCA31 patient brains. We revealed that motor-neuron disease (MND)-linked RNA-binding proteins (RBPs), TDP-43, FUS, and hnRNPA2B1, bind to and induce structural alteration of UGGAAexp. These RBPs suppress UGGAAexp-mediated toxicity in Drosophila by functioning as RNA chaperones for proper UGGAAexp folding and regulation of PPR translation. Furthermore, nontoxic short UGGAA repeat RNA suppressed mutated RBP aggregation and toxicity in MND Drosophila models. Thus, functional crosstalk of the RNA/RBP network regulates their own quality and balance, suggesting convergence of pathomechanisms in microsatellite expansion disorders and RBP proteinopathies.