The connexin 30 A88V mutant reduces cochlear gap junction expression and confers long-term protection against hearing loss

Mutations in the genes that encode the gap junction proteins connexin 26 (Cx26, encoded by GJB2) and Cx30 (GJB6) are the leading cause of hereditary hearing loss. That said, the Cx30 p.Ala88Val (A88V) mutant causes Clouston syndrome, but not hearing loss. Here, we report that the Cx30-A88V mutant, despite being toxic to inner ear-derived HEI-OC1 cells, conferred remarkable long-term protection against age-related high frequency hearing loss in Cx30(A88V/A88V) mice. During early development, there were no overt structural differences in the cochlea between genotypes, including a normal complement of hair cells; however, the supporting cell Cx30 gap junction plaques in mutant mice were reduced in size. In adulthood, Cx30(A88V/A88V) mutant mice had a reduction of cochlear Cx30 mRNA and protein, yet a full complement of hair cells. Conversely, the age-related high frequency hearing loss in Cx30(+/+) and Cx30(+/A88V) mice was due to extensive loss of outer hair cells. Our data suggest that the Cx30-A88V mutant confers long-term hearing protection and prevention of hair cell death, possibly via a feedback mechanism that leads to the reduction of total Cx30 gap junction expression in the cochlea

Stage 1 Registered Report: The relationship between handedness and language ability in children [version 1; referees: 2 approved]

Weak or inconsistent hand preference may be a risk factor for developmental language delay.  This study will test the extent to which variations in language skills are associated with the strength of hand preference. Data are drawn from a large sample (n = 569) of 6- to 7-year-old children unselected for ability, assessed at two time points, 6 months apart. Hand preference is assessed using the Quantitative Hand Preference task (QHP) and five uni-manual motor tasks. Language skills (expressive and receptive vocabulary, receptive grammar, and morphological awareness) are assessed with standardized measures. If weak cerebral lateralisation (as assessed by the QHP task) is a risk factor for language difficulties, it should be possible to detect such effects in the large representative sample of children examined here

Assessing Land Degradation/Recovery in the African Sahel from Long-Term Earth Observation Based Primary Productivity and Precipitation Relationships

The ‘rain use efficiency’ (RUE) may be defined as the ratio of above-ground net primary productivity (ANPP) to annual precipitation, and it is claimed to be a conservative property of the vegetation cover in drylands, if the vegetation cover is not subject to non-precipitation related land degradation. Consequently, RUE may be regarded as means of normalizing ANPP for the impact of annual precipitation, and as an indicator of non-precipitation related land degradation. Large scale and long term identification and monitoring of land degradation in drylands, such as the Sahel, can only be achieved by use of Earth Observation (EO) data. This paper demonstrates that the use of the standard EO-based proxy for ANPP, summed normalized difference vegetation index (NDVI) (National Oceanic and Atmospheric Administration (NOAA) Advanced Very High Resolution Radiometer (AVHRR) Global Inventory Modeling and Mapping Studies 3rd generation (GIMMS3g)) over the year (ΣNDVI), and the blended EO/rain gauge based data-set for annual precipitation (Climate Prediction Center Merged Analysis of Precipitation, CMAP) results in RUE-estimates which are highly correlated with precipitation, rendering RUE useless as a means of normalizing for the impact of annual precipitation on ANPP. By replacing ΣNDVI by a ‘small NDVI integral’, covering only the rainy season and counting only the increase of NDVI relative to some reference level, this problem is solved. Using this approach, RUE is calculated for the period 1982–2010. The result is that positive RUE-trends dominate in most of the Sahel, indicating that non-precipitation related land degradation is not a widespread phenomenon. Furthermore, it is argued that two preconditions need to be fulfilled in order to obtain meaningful results from the RUE temporal trend analysis: First, there must be a significant positive linear correlation between annual precipitation and the ANPP proxy applied. Second, there must be a near-zero correlation between RUE and annual precipitation. Thirty-seven percent of the pixels in Sahel satisfy these requirements and the paper points to a range of different reasons why this may be the case

Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication

Alterations to the gut microbiome are associated with various neurological diseases, yet evidence of causality and identity of microbiome-derived compounds that mediate gut-brain axis interaction remain elusive. Here, we identify two previously unknown bacterial metabolites 3-methyl-4-(trimethylammonio)butanoate and 4-(trimethylammonio)pentanoate, structural analogs of carnitine that are present in both gut and brain of specific pathogen–free mice but absent in germ-free mice. We demonstrate that these compounds are produced by anaerobic commensal bacteria from the family Lachnospiraceae (Clostridiales) family, colocalize with carnitine in brain white matter, and inhibit carnitine-mediated fatty acid oxidation in a murine cell culture model of central nervous system white matter. This is the first description of direct molecular inter-kingdom exchange between gut prokaryotes and mammalian brain cells, leading to inhibition of brain cell function

Microbiome-derived carnitine mimics as previously unknown mediators of gut-brain axis communication

Alterations to the gut microbiome are associated with various neurological diseases, yet evidence of causality and identity of microbiome-derived compounds that mediate gut-brain axis interaction remain elusive. Here, we identify two previously unknown bacterial metabolites 3-methyl-4-(trimethylammonio)butanoate and 4-(trimethylammonio)pentanoate, structural analogs of carnitine that are present in both gut and brain of specific pathogen-free mice but absent in germ-free mice. We demonstrate that these compounds are produced by anaerobic commensal bacteria from the family Lachnospiraceae (Clostridiales) family, colocalize with carnitine in brain white matter, and inhibit carnitine-mediated fatty acid oxidation in a murine cell culture model of central nervous system white matter. This is the first description of direct molecular inter-kingdom exchange between gut prokaryotes and mammalian brain cells, leading to inhibition of brain cell function.Additional co-authors: Emily K. Osterweil, Andrew S. MacDonald, Chris J. Schofield, Saverio Tardito, Josephine Bunch, Gillian Douce, Julia M. Edgar, RuAngelie Edrada-Ebel, Richard J. A. Goodwin, Richard Burchmore, Daniel M. Wal

Palaeogenomic analysis of black rat (Rattus rattus) reveals multiple European introductions associated with human economic history

The distribution of the black rat (Rattus rattus) has been heavily influenced by its association with humans. The dispersal history of this non-native commensal rodent across Europe, however, remains poorly understood, and different introductions may have occurred during the Roman and medieval periods. Here, in order to reconstruct the population history of European black rats, we first generate a de novo genome assembly of the black rat. We then sequence 67 ancient and three modern black rat mitogenomes, and 36 ancient and three modern nuclear genomes from archaeological sites spanning the 1st-17th centuries CE in Europe and North Africa. Analyses of our newly reported sequences, together with published mitochondrial DNA sequences, confirm that black rats were introduced into the Mediterranean and Europe from Southwest Asia. Genomic analyses of the ancient rats reveal a population turnover in temperate Europe between the 6th and 10th centuries CE, coincident with an archaeologically attested decline in the black rat population. The near disappearance and re-emergence of black rats in Europe may have been the result of the breakdown of the Roman Empire, the First Plague Pandemic, and/or post-Roman climatic cooling.Peer reviewe

Reconstructing Asian faunal introductions to eastern Africa from multi-proxy biomolecular and archaeological datasets

Human-mediated biological exchange has had global social and ecological impacts. In subS-aharan Africa, several domestic and commensal animals were introduced from Asia in the pre-modern period; however, the timing and nature of these introductions remain contentious. One model supports introduction to the eastern African coast after the mid-first millennium CE, while another posits introduction dating back to 3000 BCE. These distinct scenarios have implications for understanding the emergence of long-distance maritime connectivity, and the ecological and economic impacts of introduced species. Resolution of this longstanding debate requires new efforts, given the lack of well-dated fauna from high-precision excavations, and ambiguous osteomorphological identifications. We analysed faunal remains from 22 eastern African sites spanning a wide geographic and chronological range, and applied biomolecular techniques to confirm identifications of two Asian taxa: domestic chicken (Gallus gallus) and black rat (Rattus rattus). Our approach included ancient DNA (aDNA) analysis aided by BLAST-based bioinformatics, Zooarchaeology by Mass Spectrometry (ZooMS) collagen fingerprinting, and direct AMS (accelerator mass spectrometry) radiocarbon dating. Our results support a late, mid-first millennium CE introduction of these species. We discuss the implications of our findings for models of biological exchange, and emphasize the applicability of our approach to tropical areas with poor bone preservation

Effectiveness of a cognitive behavioural intervention for patients with undifferentiated somatoform disorder: results from the CIPRUS cluster randomized controlled trial in primary care

Objective: To examine the effectiveness of a cognitive behavioural intervention delivered by mental health nurse practitioners (MHNPs) to patients with undifferentiated somatoform disorder (USD), compared to usual care. Methods: We conducted a cluster randomized trial among primary care patients with USD comparing the intervention to usual care. The intervention consisted of six sessions with the MHNP. Primary outcome was physical functioning (RAND-36 physical component summary score). Secondary outcomes were the RAND-36 mental component summary score and the eight subscales; anxiety and depression (Hospital Anxiety and Depression Scale) and somatic symptom severity (Patient Health Questionnaire-15). Outcomes were assessed at baseline, 2, 4 and 12 months. We analysed data using linear mixed models by intention-to-treat, and investigated effect modifiers. Results: Compared to usual care (n=87), the intervention group (n=111) showed an improvement in physical functioning (mean difference 2.24 [95% CI 0.51; 3.97]; p=.011), a decrease in limitations due to physical problems (mean difference 10.82 [95% CI 2.14; 19.49]; p.=0.015) and in pain (mean difference 5.08 [95% CI 0.58; 9.57]; p=.027), over 12 months. However effect sizes were small and less clinically relevant than expected. We found no differences for anxiety, depression and somatic symptom severity. Effects were larger and clinically relevant for patients with more recent symptoms and fewer physical diseases. Conclusion: The cognitive behavioural intervention was effective in improving pain and physical functioning components of patients' health. It was particularly suitable for patients with symptoms that had been present for a limited number of years and with few comorbid physical diseases. Trial registration: The trial is registered in the Dutch Trial Registry, www.trialregister.nl, under NTR4686