General Synthesis of Conformationally Constrained Noncanonical Amino Acids with C(sp3)-Rich Benzene Bioisosteres.

Recent years have seen novel modalities emerge for the treatment of human diseases resulting in an increase in beyond rule of 5 (bRo5) chemical matter. As a result, synthetic innovations aiming to enable rapid access to complex bRo5 molecular entities have become increasingly valuable for medicinal chemists' toolkits. Herein, we report the general synthesis of a new class of noncanonical amino acids (ncAA) with a cyclopropyl backbone to achieve conformational constraint and bearing C(sp3)-rich benzene bioisosteres. We also demonstrate preliminary studies toward utilities of these ncAA as building blocks for medicinal chemistry research.

Whole-chromosome hitchhiking driven by a male-killing endosymbiont.

Neo-sex chromosomes are found in many taxa, but the forces driving their emergence and spread are poorly understood. The female-specific neo-W chromosome of the African monarch (or queen) butterfly Danaus chrysippus presents an intriguing case study because it is restricted to a single 'contact zone' population, involves a putative colour patterning supergene, and co-occurs with infection by the male-killing endosymbiont Spiroplasma. We investigated the origin and evolution of this system using whole genome sequencing. We first identify the 'BC supergene', a broad region of suppressed recombination across nearly half a chromosome, which links two colour patterning loci. Association analysis suggests that the genes yellow and arrow in this region control the forewing colour pattern differences between D. chrysippus subspecies. We then show that the same chromosome has recently formed a neo-W that has spread through the contact zone within approximately 2,200 years. We also assembled the genome of the male-killing Spiroplasma, and find that it shows perfect genealogical congruence with the neo-W, suggesting that the neo-W has hitchhiked to high frequency as the male-killer has spread through the population. The complete absence of female crossing-over in the Lepidoptera causes whole-chromosome hitchhiking of a single neo-W haplotype, carrying a single allele of the BC supergene and dragging multiple non-synonymous mutations to high frequency. This has created a population of infected females that all carry the same recessive colour patterning allele, making the phenotypes of each successive generation highly dependent on uninfected male immigrants. Our findings show how hitchhiking can occur between the physically unlinked genomes of host and endosymbiont, with dramatic consequences.

A Dyadic Investigation of Depressed Affect and Interspousal Behavior in Couples With Chronic Back Pain.

BACKGROUND: Depression and marital discord are characteristic not only of individuals with chronic low back pain (ICPs) but also of their spouses. PURPOSE: We examined actor-partner interdependence models to evaluate associations among depressed affect and criticism and support of partners at the same time point (concurrent effects) and 3 hr later (lagged effects). Fully dyadic models were used to account for both within-person and cross-spouse associations among depressed affect, criticism, and support for ICPs and spouses. We also examined the direction of the relationships (depressed affect predicting behavior and behavior predicting depressed affect) all while controlling for pain intensity, pain behavior, and the prior dependent variable. METHODS: ICPs (n = 105) and their spouses completed electronic diary measures of depressed affect and behavior (criticism and support) five times a day for 2 weeks. Hierarchical linear modeling with person-mean centering was used for data analysis. RESULTS: Within the same 3 hr epoch, more depressed affect was related to higher criticism and generally less support. Lagged analyses suggested bidirectional relationships between spouse's own depressed affect and spouse's own criticism of ICPs. Spouse depressed affect was also associated with decreased support received from ICPs. Pain behavior and pain intensity were also related to depressed affect, criticism, and support especially concurrently. CONCLUSIONS: Theories and interventions need to address not only ICP depressed affect but also spouse depressed affect, as spouse depressed affect may be a stress generating precursor to criticism and support.

Global biogeography of warning coloration in the butterfly Danaus chrysippus.

Warning coloration provides a textbook example of natural selection, but the frequent observation of polymorphism in aposematic species presents an evolutionary puzzle. We investigated biogeography and polymorphism of warning patterns in the widespread butterfly Danaus chrysippus using records from citizen science (n = 5467), museums (n = 8864) and fieldwork (n = 2586). We find that polymorphism in three traits controlled by known mendelian loci is extensive. Broad allele frequency clines, hundreds of kilometres wide, suggest a balance between long-range dispersal and predation of unfamiliar morphs. Mismatched clines for the white hindwing and forewing tip in East Africa are consistent with a previous finding that the black wingtip allele has spread recently in the region through hitchhiking with a heritable endosymbiont. Light/dark background coloration shows more extensive polymorphism. The darker genotype is more common in cooler regions, possibly reflecting a trade-off between thermoregulation and predator warning. Overall, our findings show how studying local adaptation at the global scale provides a more complete picture of the evolutionary forces involved.

Real world SOF/VEL/VOX retreatment outcomes and viral resistance analysis for HCV patients with prior failure to DAA therapy.

Sustained viral response (SVR) rates for direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection routinely exceed 95%. However, a small number of patients require retreatment. Sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is a potent DAA combination primarily used for the retreatment of patients who failed by DAA therapies. Here we evaluate retreatment outcomes and the effects of resistance-associated substitutions (RAS) in a real-world cohort, including a large number of genotype (GT)3 infected patients. 144 patients from the UK were retreated with SOF/VEL/VOX following virologic failure with first-line DAA treatment regimens. Full-length HCV genome sequencing was performed prior to retreatment with SOF/VEL/VOX. HCV subtypes were assigned and RAS relevant to each genotype were identified. GT1a and GT3a each made up 38% (GT1a n = 55, GT3a n = 54) of the cohort. 40% (n = 58) of patients had liver cirrhosis of whom 7% (n = 4) were decompensated, 10% (n = 14) had hepatocellular carcinoma (HCC) and 8% (n = 12) had received a liver transplant prior to retreatment. The overall retreatment SVR12 rate was 90% (129/144). On univariate analysis, GT3 infection (50/62; SVR = 81%, p = .009), cirrhosis (47/58; SVR = 81%, p = .01) and prior treatment with SOF/VEL (12/17; SVR = 71%, p = .02) or SOF+DCV (14/19; SVR = 74%, p = .012) were significantly associated with retreatment failure, but existence of pre-retreatment RAS was not when viral genotype was taken into account. Retreatment with SOF/VEL/VOX is very successful for non-GT3-infected patients. However, for GT3-infected patients, particularly those with cirrhosis and failed by initial SOF/VEL treatment, SVR rates were significantly lower and alternative retreatment regimens should be considered.

Hepatitis B virus (HBV) viral load, liver and renal function in adults treated with tenofovir disoproxil fumarate (TDF) vs. untreated: a retrospective longitudinal UK cohort study.

BACKGROUND: Current clinical guidelines recommend treating chronic hepatitis B virus (HBV) infection in a minority of cases, but there are relatively scarce data on evolution or progression of liver inflammation and fibrosis in cases of chronic HBV (CHB) that do not meet treatment criteria. We aimed to assess the impact of TDF on liver disease, and the risk of renal impairment in treated CHB patients in comparison to untreated patients. METHODS: We studied a longitudinal ethnically diverse CHB cohort in the UK attending out-patient clinics between 2005 and 2018. We examined TDF treatment (vs. untreated) as the main exposure, with HBV DNA viral load (VL), ALT, elastography scores and eGFR as the main outcomes, using paired tests and mixed effects model for longitudinal measurements. Additionally, decline of eGFR during follow-up was quantified within individuals by thresholds based on clinical guidelines. Baseline was defined as treatment initiation for TDF group and the beginning of clinical follow-up for untreated group respectively. RESULTS: We included 206 adults (60 on TDF, 146 untreated), with a median ± IQR follow-up duration of 3.3 ± 2.8 years. The TDF group was significantly older (median age 39 vs. 35 years, p = 0.004) and more likely to be male (63% vs. 47%, p = 0.04) compared to the untreated group. Baseline difference between TDF and untreated groups reflected treatment eligibility criteria. As expected, VL and ALT declined significantly over time in TDF-treated patients. Elastography scores normalised during treatment in the TDF group reflecting regression of inflammation and/or fibrosis. However, 6/81 (7.4%) of untreated patients had a progression of fibrosis stage from F0-F1 to F2 or F3. There was no evidence of difference in rates or incidence of renal impairment during follow-up in the TDF vs. untreated group. CONCLUSIONS: Risk of liver inflammation and fibrosis may be raised in untreated patients compared to those receiving TDF, and TDF may benefit a larger percentage of the CHB population.

Radioactive Source Localisation via Projective Linear Reconstruction.

Radiation mapping, through the detection of ionising gamma-ray emissions, is an important technique used across the nuclear industry to characterise environments over a range of length scales. In complex scenarios, the precise localisation and activity of radiological sources becomes difficult to determine due to the inability to directly image gamma photon emissions. This is a result of the potentially unknown number of sources combined with uncertainties associated with the source-detector separation-causing an apparent 'blurring' of the as-detected radiation field relative to the true distribution. Accurate delimitation of distinct sources is important for decommissioning, waste processing, and homeland security. Therefore, methods for estimating the precise, 'true' solution from radiation mapping measurements are required. Herein is presented a computational method of enhanced radiological source localisation from scanning survey measurements conducted with a robotic arm. The procedure uses an experimentally derived Detector Response Function (DRF) to perform a randomised-Kaczmarz deconvolution from robotically acquired radiation field measurements. The performance of the process is assessed on radiation maps obtained from a series of emulated waste processing scenarios. The results demonstrate a Projective Linear Reconstruction (PLR) algorithm can successfully locate a series of point sources to within 2 cm of the true locations, corresponding to resolution enhancements of between 5× and 10×.

Element-Specific Detection of Sub-Nanosecond Spin-Transfer Torque in a Nanomagnet Ensemble.

Spin currents can exert spin-transfer torques on magnetic systems even in the limit of vanishingly small net magnetization, as recently shown for antiferromagnets. Here, we experimentally show that a spin-transfer torque is operative in a macroscopic ensemble of weakly interacting, randomly magnetized Co nanomagnets. We employ element- and time-resolved X-ray ferromagnetic resonance (XFMR) spectroscopy to directly detect subnanosecond dynamics of the Co nanomagnets, excited into precession with cone angle ≳0.003° by an oscillating spin current. XFMR measurements reveal that as the net moment of the ensemble decreases, the strength of the spin-transfer torque increases relative to those of magnetic field torques. Our findings point to spin-transfer torque as an effective way to manipulate the state of nanomagnet ensembles at subnanosecond time scales.

Indigenous knowledge of South African bird and rangeland ecology is effective for informing conservation science.

South Africa's communal rangelands constitute ~25% of the country's land cover and are largely managed for livestock grazing. These habitats play an important role in rural livelihoods and cultural practices. Using semi-structured interviews, we documented indigenous local ecological knowledge (LEK) held by rural dwellers linked to natural resource utilisation, environmental health and cultural keystone indicator species (CKIS) in the grassland communities of southern KwaZulu-Natal, South Africa. Our main objective was to examine the ability for LEK to inform conservation management. We found that people who were heavily reliant on natural resources attained a higher LEK score, indicating a greater breadth of ecological knowledge, which in turn shaped their perceptions of environmental change. Community members confirmed the presence of conservation concern species within this area, highlighting the limitations of only using citizen science databases for conservation management, as their observations within these databases are biased towards major road routes and protected or urban areas. LEK can play an important role in identifying habitats crucial to species' persistence and delineating population trends over time. Our surveys highlighted the importance of the Southern Ground-hornbill Bucorvus leadbeateri as a CKIS that acts as an early warning system of changing weather, notably rain. However, LEK is context-specific, and some CKIS species such as the Southern Ground-hornbill have wide distribution ranges. Consequently, the cultural associations and implications differ based on local belief systems that are often defined by the language spoken and the community's geographical location. Our study demonstrated the importance of including indigenous LEK in conservation planning for threatened species and habitats and the importance of traditional family values responsible for transferring oral knowledge.

Conductivitylike Gilbert Damping due to Intraband Scattering in Epitaxial Iron.

Confirming the origin of Gilbert damping by experiment has remained a challenge for many decades, even for simple ferromagnetic metals. Here, we experimentally identify Gilbert damping that increases with decreasing electronic scattering in epitaxial thin films of pure Fe. This observation of conductivitylike damping, which cannot be accounted for by classical eddy-current loss, is in excellent quantitative agreement with theoretical predictions of Gilbert damping due to intraband scattering. Our results resolve the long-standing question about a fundamental damping mechanism and offer hints for engineering low-loss magnetic metals for cryogenic spintronics and quantum devices.

Open-Label Clinical Trials of Oral Pulse Dexamethasone for Adults with Idiopathic Nephrotic Syndrome.

BACKGROUND: In adults with primary focal segmental glomerulosclerosis (FSGS), daily prednisone may induce complete remissions (CR) and partial remissions (PR), but relapses are frequent and adverse events are common. METHODS: We carried out 2 open-label, uncontrolled trials to explore the efficacy and tolerability of pulse oral dexamethasone as an alternative to daily prednisone. We enrolled adult patients with proteinuria > 3.5 g/day despite the use of renin-angiotensin-aldosterone blockade. In the first trial, we enrolled 14 subjects with FSGS and administered 4 dexamethasone doses (25 mg/m2) daily for 4 days, repeated every 28 days over 32 weeks. The second trial involved a more intensive regimen. Eight subjects received 4 dexamethasone doses of 50 mg/m2 every 4 weeks for 12 weeks, followed by 4 doses of 25 mg/m2 every 4 weeks for 36 weeks; subjects were randomized to 2 doses every 2 weeks or 4 doses every 4 weeks. RESULTS: In the first trial, we enrolled 13 subjects with FSGS and 1 with minimal change disease and found a combined CR and PR rate of 36%. In the second trial, we enrolled 8 subjects. The combined CR and PR rate was 29%. Analysis combining both trials showed a combined CR and PR rate of 33%. Adverse events were observed in 32% of subjects, with mood symptoms being most common. There were no serious adverse events related to the study. CONCLUSION: We conclude that high dose oral dexamethasone is well tolerated by adults with idiopathic nephrotic syndrome and may have some efficacy.

Depressive Symptoms, Criticism, and Counter-Criticism in Marital Interactions.

Although people with depressive symptoms face criticism, hostility, and rejection in their close relationships, we do not know how they respond. Following interpersonal theories of depression, it might be expected that depressive symptoms would be associated with a tendency to receive and also to express criticism toward one's spouse, and that at least some of this criticism would be a contingent response to criticism received (i.e., "counter-criticism"). However, other research has determined that depressive symptoms/behaviors suppress partner criticism, suggesting that depressed people might respond to partner criticism similarly, by subsequently expressing less criticism. In a sample of 112 married couples, partial correlations, regressions, and Actor-Partner Interdependence Modeling indicated that lower criticism and counter-criticism expression during a laboratory marital interaction task was associated with higher depressive symptoms, especially when such individuals were clinically depressed. Furthermore, during a separate and private Five-Minute Speech Sample, lower criticism by partners was associated with higher depressive symptoms, especially when those who chose the interaction topic were also clinically depressed. All analyses controlled for relationship adjustment. These results suggest that spouses with higher depressive symptoms and clinical depression diagnoses may be suppressing otherwise ordinary criticism expression toward their nondepressed partners; furthermore, nondepressed partners of depressed people are especially likely to display less criticism toward their spouse in a private task.

Aunque las personas con síntomas depresivos enfrentan la crítica, la hostilidad y el rechazo en sus relacionones cercanas, no sabemos cómo responden. Siguiendo las teorías intepersonales de depresión, podría esperarse que los síntomas depresivos estuvieran asociados con una tendencia a recibir y también a expresar críticas hacia el cónyuge de uno, y que por lo menos parte de esta crítica fuera una respuesta condicionada por las críticas recibidas (p. ej.: "contracrítica"). Sin embargo, otras investigaciones han determinado que las conductas o los síntomas depresivos moderan la crítica de la pareja, lo cual sugiere que las personas deprimidas podrían responder a las críticas de la pareja de forma similiar, expresando posteriormente menos críticas. En una muestra de 112 parejas casadas, las correlaciones parciales, los análisis de la regresión y el modelo de interdependencia actor-pareja (APIM) indicaron que una menor expresión de crítica y contracrítica durante una tarea de interacción conyugal en laboratorio estuvo asociada con mayores síntomas depresivos, especialmente cuando dichas personas estaban clínicamente deprimidas. Además, durante una muestra independiente y en privado de un discurso de cinco minutos, una menor expresión de crítica por parte de las parejas estuvo asociada con mayores síntomas depresivos, especialmente cuando los que eligieron el tema de interacción también estaban clínicamente deprimidos. Todos los análisis controlaron la adaptación de la relación. Estos resultados sugieren que los cónyuges con mayores síntomas depresivos y con diagnósticos de depresión clínica pueden estar suprimiendo una expresión de crítica normal hacia sus parejas no deprimidas. Además, las parejas no deprimidas de las personas deprimidas son especialmente propensas a mostrar menos críticas hacia su cónyuge en una tarea a solas.

A Short Cut to Mushrooms - Red Langur (Presbytis rubicunda) Consumption of Terrestrial Fungus.

We report the first in-depth evidence of targeted mushroom foraging in an Asian colobine. Using direct observations (2010-2018) and camera traps (2008-2018) in the Sebangau Forest, Central Kalimantan, Indonesian Borneo, we show how adult female red langurs (Presbytis rubicunda) are regularly descending to the ground to consume mushrooms. We recorded 82 counts (0.36% of all focal observations, n = 25,502) of the focal adult langur on the ground from direct observations of habituated groups, and 80 independent images/videos of red langurs on the ground were obtained from the camera traps representing 1.12% of total images (n = 7,145). Mushroom consumption took place in 4 families, representing 0.04% of total focal behaviour observations and 24.3% of total time feeding on the ground. From the camera trap photos, red langurs are spending 20% of time on the ground feeding. We speculate that mushrooms could be a supplementary food for adult female langurs as there is an increase in consumption in April and November.

Abdominal point tenderness and an impending aneurysmal rupture.

Although isolated iliac artery aneurysms are rare and occur in only 2% of patients, isolated internal iliac artery aneurysms are even more uncommon. Patients with these aneurysms require urgent vascular surgery consultation and evaluation; untreated aneurysms have a high propensity to increase in size and rupture. Providers should be aware of this critical incidental finding on CT scan and MRI and know when to initiate an emergency workup and therapy.

Karyotypes versus Genomes: The Nymphalid Butterflies Melitaea cinxia, Danaus plexippus, and D. chrysippus.

The number of sequenced lepidopteran genomes is increasing rapidly. However, the corresponding assemblies rarely represent whole chromosomes and generally also lack the highly repetitive W sex chromosome. Knowledge of the karyotypes can facilitate genome assembly and further our understanding of sex chromosome evolution in Lepidoptera. Here, we describe the karyotypes of the Glanville fritillary Melitaea cinxia (n = 31), the monarch Danaus plexippus (n = 30), and the African queen D. chrysippus (2n = 60 or 59, depending on the source population). We show by FISH that the telomeres are of the (TTAGG)n type, as found in most insects. M. cinxia and D. plexippus have "conventional" W chromosomes which are heterochromatic in meiotic and somatic cells. In D. chrysippus, the W is inconspicuous. Neither telomeres nor W chromosomes are represented in the published genomes of M. cinxia and D. plexippus. Representation analysis in sequenced female and male D. chrysippus genomes detected an evolutionarily old autosome-Z chromosome fusion in Danaus. Conserved synteny of whole chromosomes, so called "macro synteny", in Lepidoptera permitted us to identify the chromosomes involved in this fusion. An additional and more recent sex chromosome fusion was found in D. chrysippus by karyotype analysis and classical genetics. In a hybrid population between 2 subspecies, D. c. chrysippus and D. c. dorippus, the W chromosome was fused to an autosome that carries a wing colour locus. Thus, cytogenetics and the present state of genome data complement one another to reveal the evolutionary history of the species.

Relationships Between Sleep Quality and Pain-Related Factors for People with Chronic Low Back Pain: Tests of Reciprocal and Time of Day Effects.

BACKGROUND: Poor sleep quality among people with chronic low back pain appears to be related to worse pain, affect, poor physical function, and pain catastrophizing. The causal direction between poor sleep and pain remains an open question, however, as does whether sleep quality exerts effects on low back pain differently across the course of the day. PURPOSE: This daily diary study examined lagged temporal associations between prior night sleep quality and subsequent day pain, affect, physical function and pain catastrophizing, the reverse lagged temporal associations between prior day pain-related factors and subsequent night sleep quality, and whether the time of day during which an assessment was made moderated these temporal associations. METHODS: Chronic low back pain patients (n = 105) completed structured electronic diary assessments five times per day for 14 days. Items included patient ratings of their pain, affect, physical function, and pain catastrophizing. RESULTS: Collapsed across all observations, poorer sleep quality was significantly related to higher pain ratings, higher negative affect, lower positive affect, poorer physical function, and higher pain catastrophizing. Lagged analyses averaged across the day revealed that poorer prior night sleep quality significantly predicted greater next day patient ratings of pain, and poorer physical function and higher pain catastrophizing. Prior poorer night sleep quality significantly predicted greater reports of pain, and poorer physical function, and higher pain catastrophizing, especially during the early part of the day. Sleep quality × time of day interactions showed that poor sleepers reported high pain, and negative mood and low function uniformly across the day, whereas good sleepers reported relatively good mornings, but showed pain, affect and function levels comparable to poor sleepers by the end of the day. Analyses of the reverse causal pathway were mostly nonsignificant. CONCLUSIONS: Sleep quality appears related not only to pain intensity but also to a wide range of patient mood and function factors. A good night's sleep also appears to offer only temporary respite, suggesting that comprehensive interventions for chronic low back pain not only should include attention to sleep problems but also focus on problems with pain appraisals and coping.

A patient with a curious case of cyclical vomiting.

Cannabis-related ED visits are on the rise due to wider legalization and availability of marijuana, and habitual daily use is increasingly common. Cannabis abuse has long been associated with various short-term and long-term adverse reactions. One such reaction is cannabinoid hyperemesis syndrome: cyclical vomiting, nausea, and abdominal pain that only resolves with a warm bath or shower. Healthcare providers must understand the signs and symptoms of cannabinoid hyperemesis syndrome so the problem can be recognized early and patients avoid unnecessary testing.

1H NMR-Linked Metabolomics Analysis of Liver from a Mouse Model of NP-C1 Disease.

Clinical manifestations of Niemann-Pick type C1 (NP-C1) disease include neonatal hepatosplenomegaly and in some patients progressive liver dysfunction and failure. This study involved a 1H NMR-linked metabolomics analysis of liver samples collected from a NP-C1 disease mutant mouse model in order to explore time-dependent imbalances in metabolic pathways associated with NP-C1 liver dysfunction, including fibrosis. NP-C1 mutant (Npc1-/-; NP-C1), control (Npc1+/+; WT), and NP-C1 heterozygous mice (Npc1+/-; HET) were generated from heterozygote matings. Aqueous extracts of these liver samples collected at time points of 3, 6, 9, and 11 weeks were subjected to high-resolution NMR analysis, and multivariate (MV) metabolomics analyses of data sets acquired were performed. A MV random forests (RFs) model effectively discriminated between NP-C1 and a combined WT/HET hepatic NMR profiles with very high predictive accuracy and reliability. Key distinguishing features included significant upregulations in the hepatic concentrations of phenylalanine, tyrosine, glutamate, lysine/ornithine, valine, threonine, and hypotaurine/methionine, and diminished levels of nicotinate/niacinamide, inosine, phosphoenolpyruvate, and 3-hydroxyphenylacetate. Quantitative pathway topological analysis confirmed that imbalances in tyrosine biosynthesis, and hepatic phenylalanine, tyrosine, glutamate/glutamine, and nicotinate/niacinamide metabolism were involved in the pathogenesis of NP-C1 disease-associated liver dysfunction/damage. 1H NMR-linked metabolomics analysis provides valuable biomarker information regarding hepatic dysfunction or damage in NP-C1 disease.

Immune dysfunction in Niemann-Pick disease type C.

Lysosomal storage diseases are inherited monogenic disorders in which lysosome function is compromised. Although individually very rare, they occur at a collective frequency of approximately one in five thousand live births and usually have catastrophic consequences for health. The lysosomal storage diseases Niemann-Pick disease type C (NPC) is caused by mutations predominantly in the lysosomal integral membrane protein NPC1 and clinically presents as a progressive neurodegenerative disorder. In this article we review data that demonstrate significant dysregulation of innate immunity in NPC, which occurs both in peripheral organs and the CNS. In particular pro-inflammatory responses promote disease progression and anti-inflammatory drugs provide benefit in animal models of the disease and are an attractive target for clinical intervention in this disorder. Niemann-Pick disease type C is a rare, devastating, inherited lysosomal storage disease with a unique cellular phenotype characterized by lysosomal accumulation of sphingosine, various glycosphingolipids and cholesterol and a reduction in lysosomal calcium. In this review we highlight the impact of the disease on innate immune activities in both the central nervous system (CNS) and peripheral tissues and discuss their contributions to pathology and the underlying mechanisms.

A neo-W chromosome in a tropical butterfly links colour pattern, male-killing, and speciation.

Sexually antagonistic selection can drive both the evolution of sex chromosomes and speciation itself. The tropical butterfly the African Queen, Danaus chrysippus, shows two such sexually antagonistic phenotypes, the first being sex-linked colour pattern, the second, susceptibility to a male-killing, maternally inherited mollicute, Spiroplasma ixodeti, which causes approximately 100% mortality in male eggs and first instar larvae. Importantly, this mortality is not affected by the infection status of the male parent and the horizontal transmission of Spiroplasma is unknown. In East Africa, male-killing of the Queen is prevalent in a narrow hybrid zone centred on Nairobi. This hybrid zone separates otherwise allopatric subspecies with different colour patterns. Here we show that a neo-W chromosome, a fusion between the W (female) chromosome and an autosome that controls both colour pattern and male-killing, links the two phenotypes thereby driving speciation across the hybrid zone. Studies of the population genetics of the neo-W around Nairobi show that the interaction between colour pattern and male-killer susceptibility restricts gene flow between two subspecies of D. chrysippus Our results demonstrate how a complex interplay between sex, colour pattern, male-killing, and a neo-W chromosome, has set up a genetic 'sink' that keeps the two subspecies apart. The association between the neo-W and male-killing thus provides a 'smoking gun' for an ongoing speciation process.