Rapid Genetic Isolation Among Four Lineages Of Silene nutans.

Speciation is the process leading to the emergence of new species. While being usually progressive, it can sometimes be fast with rapid emergence of reproductive barriers leading to high level of reproductive isolation. Some reproductive barriers might leave signatures in the genome, through elevated level of genetic differentiation at specific loci. Similar signatures might also be the results of linked selection acting in low recombination regions. Nottingham catchfly (Silene nutans) is a Caryophyllaceae species composed of four genetically differentiated lineages for which strong and asymmetric levels of reproductive isolation have been identified. Using population transcriptomic data from several individuals of the four lineages, we inferred the best evo-demographic scenario leading to the current reproductive isolation of these four lineages. We also tested whether loci exhibiting high level of genetic differentiation represented barrier loci or were located in low recombination regions, evolving under strong influence of linked selection. Overall, the four lineages of S. nutans have diverged in strict isolation, likely during the different glacial period, through migration in distinct glacial refugia. Speciation between these four lineages appeared to be particularly fast, likely due to fast evolving plastid genome accelerating plastid-nuclear co-evolution and the probability of plastid-nuclear incompatibilities in inter-lineage hybrids.

Compound heterozygous mutations in the kinase domain of IKKα lead to immunodeficiency and immune dysregulation.

IKKα, encoded by CHUK , is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKß. Absence of IKKα cause fetal encasement syndrome in human, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and cause combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features. We showed that both variants were loss-of-function. Non-canonical NF-κB activation was profoundly diminished in stromal and immune cells while the canonical pathway was partially impaired. Reintroducing wild-type CHUK restored non-canonical NF-κB activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies. Thus, this is the first case of bi-allelic CHUK mutations disrupting IKKα kinase function, broadening non-canonical NF-κB defect understanding and suggesting IKKα's role in canonical NF-κB target gene expression in human.

Inferring the Demographic History and Inheritance Mode of Tetraploid Species Using ABC.

Genomic patterns of diversity and divergence are impacted by certain life history traits, reproductive systems, and demographic history. The latter is characterized by fluctuations in population sizes over time, as well as by temporal patterns of introgression. For a given organism, identifying a demographic history that deviates from the standard neutral model allows a better understanding of its evolution but also helps to reduce the risk of false positives when screening for molecular targets of natural selection. Tetraploid organisms and beyond have demographic histories that are complicated by the mode of polyploidization, the mode of inheritance, and different scenarios of gene flow between sub-genomes and diploid parental species. Here we provide guidelines for experimenters wishing to address these issues through a flexible statistical framework: approximate Bayesian computation (ABC). The emphasis is on the general philosophy of the approach to encourage future users to exploit the enormous flexibility of ABC beyond the limitations imposed by generalist data analysis pipelines.

Radiation and hybridization underpin the spread of the fire ant social supergene.

Supergenes are clusters of tightly linked genes that jointly produce complex phenotypes. Although widespread in nature, how such genomic elements are formed and how they spread are in most cases unclear. In the fire ant Solenopsis invicta and closely related species, a "social supergene controls whether a colony maintains one or multiple queens. Here, we show that the three inversions constituting the Social b (Sb) supergene emerged sequentially during the separation of the ancestral lineages of S. invicta and Solenopsis richteri. The two first inversions arose in the ancestral population of both species, while the third one arose in the S. richteri lineage. Once completely assembled in the S. richteri lineage, the supergene first introgressed into S. invicta, and from there into the other species of the socially polymorphic group of South American fire ant species. Surprisingly, the introgression of this large and important genomic element occurred despite recent hybridization being uncommon between several of the species. These results highlight how supergenes can readily move across species boundaries, possibly because of fitness benefits they provide and/or expression of selfish properties favoring their transmission.

Skin Testing and Drug Provocation Tests in Epidermal Necrolysis: A French Experience.

BACKGROUND: There are limited data on the use of skin testing, other than patch testing, and challenges in the evaluation of epidermal necrolysis (EN), including Stevens-Johnson syndrome and toxic epidermal necrolysis. OBJECTIVE: To report a French multicenter experience in skin testing and challenges in EN, and investigate the factors associated with tests' positivity. METHODS: All patients who were evaluated by patch tests (PTs), skin prick tests, intradermal tests (IDTs), or drug provocation tests (DPTs) for EN between 2010 and 2020 were retrospectively included through 2 French drug reaction networks. RESULTS: In total, 113 patients were included from 8 centers. Median (interquartile range) time from EN to hypersensitivity workup was 7.9 months (5.1-15 months). All patients had PTs, 17 (15%) had skin prick tests or IDTs with delayed readings and 32 (28.3%) had DPTs. One mild reaction occurred after a DPT. Overall, 22 patients (19.5%) had positive PTs, and the only factors associated with positivity were Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN) score and drug class. Only 1 IDT was positive but considered irrelevant. The DPTs were never performed to prove responsibility of a highly suspected drug but were used to confirm current tolerance of needed medications. CONCLUSIONS: Allergological workup in EN, performed by specialists involved in EN, seems safe. Skin tests, although of limited sensitivity, can be helpful for considering the reintroduction of essential drugs according to a benefit-to-risk decision. We propose an algorithm for approaching hypersensitivity testing in patients with EN, to be adapted to each patient.

Searching for genetic evidence of demographic decline in an arctic seabird: beware of overlapping generations.

Genetic data are useful for detecting sudden population declines in species that are difficult to study in the field. Yet this indirect approach has its own drawbacks, including population structure, mutation patterns, and generation overlap. The ivory gull (Pagophila eburnea), a long-lived Arctic seabird, is currently suffering from rapid alteration of its primary habitat (i.e., sea ice), and dramatic climatic events affecting reproduction and recruitment. However, ivory gulls live in remote areas, and it is difficult to assess the population trend of the species across its distribution. Here we present complementary microsatellite- and SNP-based genetic analyses to test a recent bottleneck genetic signal in ivory gulls over a large portion of their distribution. With attention to the potential effects of population structure, mutation patterns, and sample size, we found no significant signatures of population decline worldwide. At a finer scale, we found a significant bottleneck signal at one location in Canada. These results were compared with predictions from simulations showing how generation time and generation overlap can delay and reduce the bottleneck microsatellite heterozygosity excess signal. The consistency of the results obtained with independent methods strongly indicates that the species shows no genetic evidence of an overall decline in population size. However, drawing conclusions related to the species' population trends will require a better understanding of the effect of age structure in long-lived species. In addition, estimates of the effective global population size of ivory gulls were surprisingly low (~1000 ind.), suggesting that the evolutionary potential of the species is not assured.

Convergent morphology and divergent phenology promote the coexistence of Morpho butterfly species.

The coexistence of closely-related species in sympatry is puzzling because ecological niche proximity imposes strong competition and reproductive interference. A striking example is the widespread wing pattern convergence of several blue-banded Morpho butterfly species with overlapping ranges of distribution. Here we perform a series of field experiments using flying Morpho dummies placed in a natural habitat. We show that similarity in wing colour pattern indeed leads to interspecific territoriality and courtship among sympatric species. In spite of such behavioural interference, demographic inference from genomic data shows that sympatric closely-related Morpho species are genetically isolated. Mark-recapture experiments in the two most closely-related species unravel a strong temporal segregation in patrolling activity of males. Such divergence in phenology reduces the costs of reproductive interference while simultaneously preserving the benefits of convergence in non-reproductive traits in response to common ecological pressures. Henceforth, the evolution of multiple traits may favour species diversification in sympatry by partitioning niche in different dimensions.

Evaluation of Thalidomide Treatment of Patients With Chronic Erythema Multiforme: A Multicenter Retrospective Cohort Study.

IMPORTANCE: Erythema multiforme (EM) may become long term, with a recurrent or persistent course. First-line treatment for chronic EM is valaciclovir. There is no consensus for selection of second-line treatment of chronic EM. OBJECTIVE: The aim of this study was to assess the effectiveness of treatment with thalidomide for patients with chronic EM. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective national multicenter cohort study, among 68 French hospital dermatology departments contacted by e-mail, 10 reported having eligible cases. All adults aged 18 years or older under dermatology care for chronic EM (including recurrent and persistent forms) who had received thalidomide between 2010 and 2018 were included. Analyses were conducted from June 24, 2019, to December 31, 2019. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients who did not experience an EM flare within 6 months of initiating thalidomide treatment for recurrent EM or with complete clearance at 6 months for persistent EM (complete remission). RESULTS: Overall, 35 patients with chronic EM (median [range] age, 33 [15-65] years; 20 [57%] female) experienced failure of at least 1 previous treatment prior to initiating treatment with thalidomide. After 6 months of continuous thalidomide treatment, 23 (66%) were in complete remission, 5 (14%) had stopped the treatment, and 7 (20%) experienced at least 1 flare. The median (IQR) initial dose followed by remission was 50 (50-100) mg/d. Main adverse effects were asthenia (16 [46%]) and neuropathy (14 [40%]). Twenty-five (71%) of patients stopped thalidomide treatment after a median (IQR) of 12 (8-20) months owing to lack of effect (7/25 [28%]), neuropathy or another adverse effect (14/25 [56%]), or long-term complete remission (4/25 [16%]). Low-dose thalidomide, less than 50 mg every other day was sufficient in 9 of 23 (39%) of responders and was associated with less neuropathy and longer treatment duration. CONCLUSIONS AND RELEVANCE: In this cohort study, second-line therapy with thalidomide was associated with complete remission in two-thirds of the 35 patients with chronic EM. However, adverse events were a common cause of thalidomide withdrawal. In the long term, dose reduction when possible may allow for continuation by improving tolerance.

Performance of ultrasound to assess erosion progression in rheumatoid arthritis.

OBJECTIVES: To analyse the performance of ultrasonography (US) to detect bone erosion progression at the patient level and at the joint level by the US score for erosions (USSe) in early-stage and late-stage rheumatoid arthritis (RA) over a 2-year follow-up. METHODS: Clinical and demographic information was recorded at baseline, and hands and feet RX were scored according to the Sharp erosion score. USSe was performed at baseline and over 2 years of follow-up on six bilateral joints (MCP2, 3, 5; MTP2, 3, 5). Inter-examiner reproducibility was performed on 14 patients, and the smallest detectable change (SDC) was calculated. US progression was defined as a change in USSe > SDC. RESULTS: 71 patients were included: 22 (31.0 %) early RA, and 49 (69.0 %) late RA. The intra-class correlation coefficient values of the USSe for intra- and inter-examiner studies were 0.96 (CI95: 0.93-0.98), and 0.92 (CI95: 0.75-0.97), respectively. On US, erosions prevailed at baseline in MTP5 joints followed by MCP2 and MCP5 joints. With an SDC calculated at 2.3, 28 patients (39.4 %) were classified as progressors, 30 (42.3 %) were stable, and 13 (18.3 %) were regressors during the follow-up. At the joint level, erosion progression was significant on the MCP2 and MTP5 joints in early RA (p < 0.01) and on the MCP5 and MTP5 joints for all RA (p < 0.05). CONCLUSIONS: US is a highly reproducible method that is able to detect erosion progression at the patient level for both early and late RA and at the joint level (MCP2 and MTP5) for only early RA.

Population collapse in viviparid gastropods of the Lake Victoria ecoregion started before the Last Glacial Maximum.

Ecosystems of Lake Victoria and riparian communities have been strongly disrupted by the introduction of the invasive Nile perch and its fishing industry. Beyond this invasion and other recent anthropogenic stressors, the Lake Victoria ecoregion also underwent phases of pronounced aridity over the Late Pleistocene, lastly during the Last Glacial Maximum (LGM). The consequences of recent and historic environmental change have been canvassed for the adaptive radiation of haplochromine cichlids occupying the ecoregion, but their effect on freshwater invertebrate diversity remains largely unknown. Here, we use 15 microsatellite loci and approximate Bayesian computation to test whether viviparid gastropods experienced a population bottleneck during the LGM, as did cichlids. Clustering analyses support three viviparid gene pools in the Lake Victoria ecoregion, gathering specimens from 1) Lake Albert and the White Nile, 2) the Victoria Nile and Lake Kyoga and 3) Lake Victoria and tributaries. The last group contains the highest genetic diversity, but all groups have a considerable number of private alleles and are inferred to predate the LGM. Examinations of demographic history reveal a 190- to 500-fold population decline that started ~ 125-150 ka ago, thus substantially before the LGM bottleneck documented in haplochromine cichlids. Population collapses in viviparids are an order of magnitude more severe than declines in cichlids and have not been halted by the re-establishment of freshwater ecosystems since the LGM. Recent anthropogenic ecosystem deterioration is causing homogenization of previously diversified microhabitats, which may contribute to (local) extinction and enhanced gene flow among species within gene pools.

DILS: Demographic inferences with linked selection by using ABC.

We present DILS, a deployable statistical analysis platform for conducting demographic inferences with linked selection from population genomic data using an Approximate Bayesian Computation framework. DILS takes as input single-population or two-population data sets (multilocus fasta sequences) and performs three types of analyses in a hierarchical manner, identifying: (a) the best demographic model to study the importance of gene flow and population size change on the genetic patterns of polymorphism and divergence, (b) the best genomic model to determine whether the effective size Ne and migration rate N, m are heterogeneously distributed along the genome (implying linked selection) and (c) loci in genomic regions most associated with barriers to gene flow. Also available via a Web interface, an objective of DILS is to facilitate collaborative research in speciation genomics. Here, we show the performance and limitations of DILS by using simulations and finally apply the method to published data on a divergence continuum composed by 28 pairs of Mytilus mussel populations/species.

Evolution of self-incompatibility in the Brassicaceae: Lessons from a textbook example of natural selection.

Self-incompatibility (SI) is a self-recognition genetic system enforcing outcrossing in hermaphroditic flowering plants and results in one of the arguably best understood forms of natural (balancing) selection maintaining genetic variation over long evolutionary times. A rich theoretical and empirical population genetics literature has considerably clarified how the distribution of SI phenotypes translates into fitness differences among individuals by a combination of inbreeding avoidance and rare-allele advantage. At the same time, the molecular mechanisms by which self-pollen is specifically recognized and rejected have been described in exquisite details in several model organisms, such that the genotype-to-phenotype map is also pretty well understood, notably in the Brassicaceae. Here, we review recent advances in these two fronts and illustrate how the joint availability of detailed characterization of genotype-to-phenotype and phenotype-to-fitness maps on a single genetic system (plant self-incompatibility) provides the opportunity to understand the evolutionary process in a unique perspective, bringing novel insight on general questions about the emergence, maintenance, and diversification of a complex genetic system.

ACPA-positive versus ACPA-negative rheumatoid arthritis: two distinct erosive disease entities on radiography and ultrasonography.

The objective of this study is to assess the prevalence, localization, and severity of bone erosions on radiography (RX) and ultrasonography (US) according to ACPA status in patients with rheumatoid arthritis (RA). 78 patients with ACPA-positive (ACPA+) RA and 30 patients with ACPA-negative (ACPA-) RA fulfilling the ACR 1987 and/or ACR/EULAR 2010 criteria were consecutively included. On RX, a modified Sharp erosion score (SHSe) was evaluated by two blinded readers and one adjudicator for discordant cases (number of eroded joints ≤ three). On US, erosions were scored on six bilateral joints (MCP2, 3, 5; MTP2, 3, 5) with a four-point scale to calculate the total US score for erosions (USSe). The mean total SHSe and USSe were 3.7 and 4.4 times higher in the ACPA+ group than in the ACPA- group, respectively (P < 0.001). On both RX and US, the most discriminating joint between the two groups was MTP5, especially in cases with bilateral erosion. Based on multivariate analyses, ACPA + status was associated with erosive RA on RX according to the EULAR 2013 definition criteria [OR 4.4 (95% CI 1.2-16.4)], and on US according to the following two definitions: the presence of at least two eroded joint facets [OR 3.7 (95% CI 1.4-9.9)] or at least one grade 2 joint facet erosion [OR 9.0 (95% CI 2.8-28.4)]. Compared to ACPA- RA, ACPA + RA is associated independently with more severe erosive disease on RX and US. Both US and RX bilateral erosions in MTP5 joints are highly discriminant for ACPA + RA patients (97.8% in US and 100% in RX).

The opposing effects of genetic drift and Haldane's sieve on floral-morph frequencies in tristylous metapopulations.

Tristyly is a genetic floral polymorphism in which three floral morphs are maintained at equal frequencies by negative frequency-dependent selection on alleles at two interacting loci. Because dominant alleles at these loci are maintained at a lower frequency than their recessive counterparts, they are more likely to be lost by founder events and genetic drift. Here we examine the hypothesis that dominant alleles under negative frequency-dependent selection should also be more likely to re-invade populations than recessive alleles, due to Haldane's Sieve, because recessive alleles not expressed in a heterozygote state cannot benefit from positive selection when rare. We used computer simulations of tristylous metapopulations to verify that Haldane's Sieve acting on migrants into occupied demes can indeed reverse the bias in allele frequencies expected for small single tristylous populations, particularly in situations of rapid population growth following colonisation. This effect is manifest both locally and at the metapopulation level. Our study illustrates the potential effect of Haldane's Sieve in the novel context of an iconic plant sexual-system polymorphism under the influence of metapopulation dynamics.

Assessment of the effect of continuous theta burst stimulation of the motor cortex on manual dexterity in non-human primates in a direct comparison with invasive intracortical pharmacological inactivation.

Non-invasive reversible perturbation techniques of brain output such as continuous theta burst stimulation (cTBS), commonly used to modulate cortical excitability in humans, allow investigation of possible roles in functional recovery played by distinct intact cortical areas following stroke. To evaluate the potential of cTBS, the behavioural effects of this non-invasive transient perturbation of the hand representation of the primary motor cortex (M1) in non-human primates (two adult macaques) were compared with an invasive focal transient inactivation based on intracortical microinfusion of GABA-A agonist muscimol. The effects on the contralateral arm produced by cTBS or muscimol were directly compared based on a manual dexterity task performed by the monkeys, the "reach and grasp" drawer task, allowing quantitative assessment of the grip force produced between the thumb and index finger and exerted on the drawer's knob. cTBS only induced modest to moderate behavioural effects, with substantial variability on manual dexterity whereas the intracortical muscimol microinfusion completely impaired manual dexterity, producing a strong and clear cortical inhibition of the M1 hand area. In contrast, cTBS induced mixed inhibitory and facilitatory/excitatory perturbations of M1, though with predominant inhibition. Although cTBS impacted on manual dexterity, its effects appear too limited and variable in order to use it as a reliable proof of cortical vicariation mechanism (cortical area replacing another one) underlying functional recovery following a cortical lesion in the motor control domain, in contrast to potent pharmacological block generated by muscimol infusion, whose application is though limited to an animal model such as non-human primate.

Optimization of ultrasonographic examination for the diagnosis of erosive Rheumatoid Arthritis in comparison to erosive hand Osteoarthritis.

OBJECTIVE: to determine thresholds and better scenario for the diagnosis of erosive rheumatoid arthritis (RA) by ultrasonography (US) in RA in comparison to osteoarthritic (OA) patients. METHODS: Patients, prospectively included, fulfilling ACR 1987; ACR/EULAR 2010 criteria for RA or hand OA criteria. Radiographic assessment (RX): Sharp erosion score, evaluated by two blinded readers and one adjudicator for discordant cases (number of eroded joints ≤ three). Definition of eroded RX RA: EULAR 2013 Definition. In US, erosions were scored on six bilateral joints (MCP2-3, 5; MTP2-3, 5) with a four-grade scale. RESULTS: A total of 168 patients were included: 122 RA (32 early RA < 2 years; 90 late RA ≥ 2 years); 46 OA patients. On RX: 42 RA patients (6 early; 36 late) and 5 OA patients have erosive diseases (sensitivity: 34.4%, specificity: 89.1%). On US, 95 RA patients (21 early; 78 late) and 12 OA patients have erosive diseases. Considering at least two joint facets eroded (threshold 1) or at least one joint facet eroded at grade 2 (threshold 2), sensitivities were good (68 and 72.1%), specificities excellent (89.1 and 100%). With only six targeted joint facets examined (6/30), sensitivities and specificities remained good (59.8 and 60.0%) and excellent (95.6 and 100%) with threshold 1 and 2 respectively. For all scenarios, agreement between RX and US for erosive RA was excellent ranged from 88.1% to 92.8%. CONCLUSION: US erosion assessment of six targeted joint facets detected 1.7 times more erosive RA patients than RX in late and early RA with good sensitivity and excellent specificity.

Ultrasonographic criteria for the diagnosis of erosive rheumatoid arthritis using osteoarthritic patients as controls compared to validated radiographic criteria.

OBJECTIVES: The aims of this study were to compare characteristics of radiography (RX) and ultrasound (US) erosive lesions in rheumatoid arthritis (RA) and osteoarthritis (OA) patients (prevalence, topography and severity), to determine thresholds for the diagnosis of erosive RA based on US and to evaluate the performance of US and RX to establish a diagnosis of erosive RA differentiated from hand OA. METHODS: Patients fulfilling ACR 1987 and/or ACR/EULAR 2010 criteria for RA or ACR hand OA criteria were prospectively included. A modified Sharp erosion score was assessed by two blinded readers and one adjudicator for discordant cases (number of eroded joints ≤ three). Erosions in US were scored on six bilateral joints (MCP2-3, 5; MTP2-3, 5) with a four-grade scale to calculate total US score for erosions (USSe). RESULTS: A total of 168 patients were included: 122 RA (32 early RA < 2 years; 90 late RA ≥ 2 years); 46 OA patients. On RX: 42 RA patients (6 early; 36 late) and 5 OA patients were eroded according to EULAR 2013 definition criteria with sensitivity at 34.4% and specificity at 89.1%. On US, 95 RA patients (21 early; 74 late) and 12 OA patients were eroded. Considering at least two joint facets eroded or at least one joint facet eroded at grade 2 on US, sensitivities were good (68-72.1%) and specificities excellent (89.1-100%). Agreement between RX and US was excellent (90-92%). The positive and negative likehood ratios were respectively 3.16 and 0.73 for radiography and 6.64 and 0.31 for US (for two facets eroded). CONCLUSION: USSe can differentiate RA from OA in erosive disease and detect two times more patients with erosive RA than RX with excellent specificity and agreement.

Selective Recruitment of Arm Motoneurons in Nonhuman Primates Using Epidural Electrical Stimulation of the Cervical Spinal Cord.

Recovery of reaching and grasping ability is the priority for people with cervical spinal cord injury (SCI). Epidural electrical stimulation (EES) has shown promising results in improving motor control after SCI in various animal models and in humans. Notably, the application of stimulation bursts with spatiotemporal sequences that reproduce the natural activation of motoneurons restored skilled leg movements in rodent and nonhuman primate models of SCI. Here, we studied whether this conceptual framework could be transferred to the design of cervical EES protocols for the recovery of reaching and grasping in nonhuman primates. We recorded muscle activity during a reaching and grasping task in a macaque monkey and found that this task involves a stereotypical spatiotemporal map of motoneuron activation. We then characterized the specificity of a spinal implant for the delivery of EES to cervical spinal segments in the same animal. Finally, we combined these results to design a simple stimulation protocol that may reproduce natural motoneuron activation and thus facilitate upper limb movements after injury.