Novel application of behavioral assays allows dissociation of joint pathology from systemic extra-articular alterations induced by inflammatory arthritis

Introduction: Although rheumatoid arthritis (RA) is a disease of articular joints, patients often suffer from co-morbid neuropsychiatric changes, such as anxiety, that may reflect links between heightened systemic inflammation and abnormal regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we apply behavioral neuroscience methods to assess the impact of antigen-induced arthritis (AIA) on behavioral performance in wild type (WT) and interleukin-10 deficient (Il10-/-) mice. Our aim was to identify limb-specific motor impairments, as well as neuropsychological responses to inflammatory arthritis. Methods: Behavioral testing was performed longitudinally in WT and Il10-/- mice before and after the induction of arthritic joint pathology. Footprint analysis, beam walking and open field assessment determined a range of motor, exploratory and anxiety-related parameters. Specific gene changes in HPA axis tissues were analyzed using qPCR. Results: Behavioral assessment revealed transient motor and exploratory impairments in mice receiving AIA, coinciding with joint swelling. Hind limb coordination deficits were independent of joint pathology. Behavioral impairments returned to baseline by 10 days post-AIA in WT mice. Il10-/- mice demonstrated comparable levels of swelling and joint pathology as WT mice up to 15 days post-AIA, but systemic differences were evident in mRNA expression in HPA axis tissues from Il10-/- mice post-AIA. Interestingly, the behavioral profile of Il10-/- mice revealed a significantly longer time post-AIA for activity and anxiety-related behaviors to recover. Conclusions: The novel application of sensitive behavioral tasks has enabled dissociation between behaviors that occur due to transient joint-specific pathology and those generated by more subtle systemic alterations that manifest post-AIA

Post-marital residence patterns show lineage-specific evolution

Where a newly-married couple lives, termed post marital residence, varies cross-culturally and changes over time. While many factors have been proposed as drivers of this change, among them general features of human societies like warfare, migration and gendered division of subsistence labour, little is known about whether changes in residence patterns exhibit global regularities. Here, we study ethnographic observations of post-marital residence in societies from five large language families (Austronesian, Bantu, Indo-European, Pama-Nyungan and Uto-Aztecan), encompassing 371 ethnolinguistic groups ranging widely in local ecologies and lifeways, and covering over half the world?s population and geographical area. We apply Bayesian comparative methods to test the hypothesis that post-marital residence patterns have evolved in similar ways across different geographical regions. By reconstructing past post-marital residence states, we compare transition rates and models of evolution across groups, while integrating the historical descent relationships of human societies. We find that each language family possesses its own best fitting model, demonstrating that the mode and pace of post-marital residence evolution is lineage-specific rather than global

Post-marital residence patterns show lineage-specific evolution

Where a newly-married couple lives, termed post-marital residence, varies cross-culturally and changes over time. While many factors have been proposed as drivers of this change, among them general features of human societies like warfare, migration and gendered division of subsistence labour, little is known about whether changes in residence patterns exhibit global regularities. Here, we study ethnographic observations of post-marital residence in societies from five large language families (Austronesian, Bantu, Indo-European, Pama-Nyungan and Uto-Aztecan), encompassing 371 ethnolinguistic groups ranging widely in local ecologies and lifeways, and covering over half the worlds population and geographical area. We apply Bayesian comparative methods to test the hypothesis that post-marital residence patterns have evolved in similar ways across different geographical regions. By reconstructing past post-marital residence states, we compare transition rates and models of evolution across groups, while integrating the historical descent relationships of human societies. We find that each language family possesses its own best fitting model, demonstrating that the mode and pace of post-marital residence evolution is lineage-specific rather than global.We thank Laura Fortunato (Institute of Cognitive and Evolutionary Anthropology, University of Oxford, UK) and Kit Opie (Department of Anthropology, University College London, UK) for access to analyses from their published work; Lyle Campbell (Department of Linguistics, University of Hawai’i Manoa, USA) and Jane Hill (School of Anthropology, University of Arizona, USA) for cognancy coding in the Uto-Aztecan dataset; and Eilis Donnelly (Victoria University of Wellington) for assistance with summarizing the ethnographic literature of Uto-Aztecan and Pama-Nyungan speakers. This research was supported by the Royal Society of New Zealand through a Rutherford Fellowship (RDF-10-MAU-001) to M.P.C., by an Allan Wilson Centre for Molecular Ecology and Evolution grant to M.P.C. and R.G., and by an Alexander von Humboldt Stiftung fellowship to M.P.C. The Max Planck Institute for the Science of Human History funded J.C.M. to attend its 2016 Spring School on quantitative methods for studying linguistic and cultural evolution. S.M. and M.P.C. are partially supported by the New Zealand Centre of Research Excellence Te Pūnaha Matatini. R.M.R. was supported by a grant from the European Union Horizon 2020 Research and Innovation Programme (grant agreement No 644055 [ALIGNED, http://aligned-project.eu]). F.M.J. received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No 639291, Starting Grant VARIKIN), and was supported by a Leverhulme Research Fellowship (47690)

Does Lateral Transmission Obscure Inheritance in Hunter-Gatherer Languages?

In recent years, linguists have begun to increasingly rely on quantitative phylogenetic approaches to examine language evolution. Some linguists have questioned the suitability of phylogenetic approaches on the grounds that linguistic evolution is largely reticulate due to extensive lateral transmission, or borrowing, among languages. The problem may be particularly pronounced in hunter-gatherer languages, where the conventional wisdom among many linguists is that lexical borrowing rates are so high that tree building approaches cannot provide meaningful insights into evolutionary processes. However, this claim has never been systematically evaluated, in large part because suitable data were unavailable. In addition, little is known about the subsistence, demographic, ecological, and social factors that might mediate variation in rates of borrowing among languages. Here, we evaluate these claims with a large sample of hunter-gatherer languages from three regions around the world. In this study, a list of 204 basic vocabulary items was collected for 122 hunter-gatherer and small-scale cultivator languages from three ecologically diverse case study areas: northern Australia, northwest Amazonia, and California and the Great Basin. Words were rigorously coded for etymological (inheritance) status, and loan rates were calculated. Loan rate variability was examined with respect to language area, subsistence mode, and population size, density, and mobility; these results were then compared to the sample of 41 primarily agriculturalist languages in [1]. Though loan levels varied both within and among regions, they were generally low in all regions (mean 5.06%, median 2.49%, and SD 7.56), despite substantial demographic, ecological, and social variation. Amazonian levels were uniformly very low, with no language exhibiting more than 4%. Rates were low but more variable in the other two study regions, in part because of several outlier languages where rates of borrowing were especially high. High mobility, prestige asymmetries, and language shift may contribute to the high rates in these outliers. No support was found for claims that hunter-gatherer languages borrow more than agriculturalist languages. These results debunk the myth of high borrowing in hunter-gatherer languages and suggest that the evolution of these languages is governed by the same type of rules as those operating in large-scale agriculturalist speech communities. The results also show that local factors are likely to be more critical than general processes in determining high (or low) loan rates

The AMPA receptor antagonist perampanel suppresses epileptic activity in human focal cortical dysplasia

Focal cortical dysplasia (FCD) is one of the most common malformations causing refractory epilepsy. Dysregulation of glutamatergic systems plays a critical role in the hyperexcitability of dysplastic neurons in FCD lesions. The pharmacoresistant nature of epilepsy associated with FCD may be due to a lack of well tolerated and precise antiepileptic drugs that can target glutamate receptors. Here, for the first time in human FCD brain slices, we show that the established, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, perampanel has potent antiepileptic action. Moreover, we demonstrate that this effect is due to a reduction in burst firing behavior in human FCD microcircuits. These data support a potential role for the treatment of refractory epilepsy associated with FCD in human patients

Global diversity and antimicrobial resistance of typhoid fever pathogens: insights from a meta-analysis of 13,000 Salmonella Typhi genomes

Background: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). Methods: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. Results: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal ‘sentinel’ surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. Conclusions: The consortium’s aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies

Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis

Ectopic lymphoid-like structures (ELSs) reminiscent of secondary lymphoid organs often develop at sites of chronic inflammation where they contribute to immune-mediated pathology. Through evaluation of synovial tissues from rheumatoid arthritis (RA) patients, we now show that low interleukin-27 (IL-27) expression corresponds with an increased incidence of ELS and gene signatures associated with their development and activity. The presence of synovial ELS was also noted in mice deficient in the IL-27 receptor (IL-27R) after the onset of inflammatory arthritis. Here, pathology was associated with increased synovial expression of pro-inflammatory cytokines, homeostatic chemokines, and transcriptional regulators linked with lymphoid neogenesis. In both clinical and experimental RA, synovial ELS coincided with the heightened local expression of cytokines and transcription factors of the Th17 and T follicular helper (Tfh) cell lineages, and included podoplanin-expressing T cells within lymphoid aggregates. IL-27 inhibited the differentiation of podoplanin-expressing Th17 cells, and an increased number of these cells were observed in IL-27R–deficient mice with inflammatory arthritis. Thus, IL-27 appears to negatively regulate ELS development in RA through control of effector T cells. These studies open new opportunities for patient stratification and treatment

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead