Taxonomic assessment of two wild house mouse subspecies using whole-genome sequencing.

The house mouse species complex (Mus musculus) is comprised of three primary subspecies. A large number of secondary subspecies have also been suggested on the basis of divergent morphology and molecular variation at limited numbers of markers. While the phylogenetic relationships among the primary M. musculus subspecies are well-defined, relationships among secondary subspecies and between secondary and primary subspecies remain less clear. Here, we integrate de novo genome sequencing of museum-stored specimens of house mice from one secondary subspecies (M. m. bactrianus) and publicly available genome sequences of house mice previously characterized as M. m. helgolandicus, with whole genome sequences from diverse representatives of the three primary house mouse subspecies. We show that mice assigned to the secondary M. m. bactrianus and M. m. helgolandicus subspecies are not genetically differentiated from M. m. castaneus and M. m. domesticus, respectively. Overall, our work suggests that the M. m. bactrianus and M. m. helgolandicus subspecies are not well-justified taxonomic entities, emphasizing the importance of leveraging whole-genome sequence data to inform subspecies designations. Additionally, our investigation provides tailored experimental procedures for generating whole genome sequences from air-dried mouse skins, along with key genomic resources to inform future genomic studies of wild mouse diversity.

Media discourse regarding COVID-19 vaccinations for children aged 5 to 11 in Australia, Canada, the United Kingdom and the United States of America: a comparative analysis using the Narrative Policy Framework.

BACKGROUND: Media narratives can shape public opinion and action, influencing people's perceptions and action regarding uptake of paediatric COVID-19 vaccines. COVID-19 has occurred at a time where 'infodemics', 'misinformation', and 'disinformation' are present, and as a result the COVID-19 response has suffered. OBJECTIVE: To investigate how narratives about paediatric COVID-19 vaccines have unfolded in the media of four English-speaking countries; USA, Australia, Canada and the UK. METHODS: The Narrative Policy Framework (NPF) was used to guide the comparative analyses of the major print and online news agencies' media regarding COVID-19 vaccines for the 5 to 11 year old age group. Data were sought using systematic searching on Factiva of four key phases of the paediatric vaccine approval and roll-out. RESULTS: 400 articles (287 for USA, 40 for Australia, 60 for Canada, and 13 for the United Kingdom) fit the search criteria and were included. Using the NPF, the following were identified in each of the articles: hero, villain, victim, plot. The USA was the earliest to vaccinate children, and other countries' media often lauded the USA for this. Australian and Canadian media narratives about 5-11 year old vaccines were commonly about protecting vulnerable people in society, whereas the USA and the UK narratives focused more on the vaccine helping children get back to school. All four countries focused on the 5-11 year old vaccine as being key to 'ending' the pandemic. Australian and Canadian narratives frequently compared vaccine roll-outs across states/provinces, and bemoaned local progress in vaccine delivery in comparison to other countries globally. Canadian and USA narratives highlighted the 'infodemic' about COVID-19 and disinformation regarding child vaccines as impeding uptake. All four of USA, Australia, UK, and Canada used war imagery in reporting about COVID-19 vaccines for children. The advent of the Omicron variant demonstrated that populations were fatigued by COVID-19 and the media reporting increasingly blamed those who were not vaccinated. The UK media narrative was unique in that it frequently described vaccinating children as a distraction from adult COVID-19 vaccination efforts. The USA and Canada had narratives expressing anger about potential vaccine passports for children. In Australia, general practitioners (GPs) were enveloped in the language of heroism. And lastly, the Canadian narrative was unique in expressing the desire to forgo adult COVID-19 vaccine 'boosters', as well as paediatric COVID-19 vaccines in order to ensure other adults globally could receive their initial vaccines. CONCLUSIONS: Public health emergencies require clear, compelling and above all, accurate communication. The stories told in this pandemic are compelling because they contain the classic elements of a narrative, however they can be reductive and inaccurate.

A Convenient, Rapid, Conventional Heating Route to MIDA Boronates.

A cheap, conventional, sealed heating reactor proved to be a useful alternative to a microwave reactor in the synthesis of a >20-member MIDA boronate library (MIDA = N-methyliminodiacetic acid). Reaction times were 10 min and work-ups were minimal, saving on energy and solvent usage.

Time-Resolved Raman Spectroscopy of Polaron Formation in a Polymer Photocatalyst.

Polymer photocatalysts are a synthetically diverse class of materials that can be used for the production of solar fuels such as H2, but the underlying mechanisms by which they operate are poorly understood. Time-resolved vibrational spectroscopy provides a powerful structure-specific probe of photogenerated species. Here we report the use of time-resolved resonance Raman (TR3) spectroscopy to study the formation of polaron pairs and electron polarons in one of the most active linear polymer photocatalysts for H2 production, poly(dibenzo[b,d]thiophene sulfone), P10. We identify that polaron-pair formation prior to thermalization of the initially generated excited states is an important pathway for the generation of long-lived photoelectrons.

A comparison of animal color measurements using a commercially available digital color sensor and photograph analysis.

An animal's pelage, feather, or skin color can serve a variety of functions, so it is important to have multiple standardized methods for measuring color. One of the most common and reliable methods for measuring animal coloration is the use of standardized digital photographs of animals. New technology in the form of a commercially available handheld digital color sensor could provide an alternative to photography-based animal color measurements. To determine whether a digital color sensor could be used to measure animal coloration, we tested the ability of a digital color sensor to measure coloration of mammalian, avian, and lepidopteran museums specimens. We compared results from the sensor to measurements taken using traditional photography methods. Our study yielded significant differences between photography-based and digital color sensor measurements of brightness (light to dark) and colors along the green to red spectrum. There was no difference between photographs and the digital color sensor measurements for colors along the blue to yellow spectrum. The average difference in recorded color (ΔE) by the 2 methods was above the threshold at which humans can perceive a difference. There were significant correlations between the sensor and photographs for all measurements indicating that the sensor is an effective animal coloration measuring tool. However, the sensor's small aperture and narrow light spectrum range designed for human-vision limit its value for ecological research. We discuss the conditions in which a digital color sensor can be an effective tool for measuring animal coloration in both laboratory settings and in the field.

Cannabinoids and the endocannabinoid system in anxiety, depression, and dysregulation of emotion in humans.

PURPOSE OF REVIEW: This review is to summarize most recent evidence published in the last 18 months on medical and recreational use of cannabis and cannabinoids in relation to anxiety, depression (unipolar and bipolar), and dysregulation of emotions as part of posttraumatic stress disorders (PTSD) and emotionally instable personality disorders. It also covers the investigation of endocannabinoids as potential biomarkers in these conditions. This is important with increasing medicinal use of cannabinoids and growing social tolerance towards recreational cannabis use. RECENT FINDINGS: There is some recent evidence suggesting cannabinoids, cannabidiol or cannabidiol-enriched cannabis preparations have anxiolytic properties. In addition, depression may be worsened by cannabis use, however, randomized controlled trials (RCT) are lacking. New evidence also suggests that cannabidiol or cannabidiol-enriched cannabis use for PTSD and emotion regulation can induce hyporesponse to fear and stress. Further, several lines of evidence point to the endocannabinoid system as a key player in some of the reviewed disorders, in particular anxiety and PTSD. SUMMARY: The most recent evidence for a therapeutic use of cannabinoids in the reviewed conditions is weak and lacking well designed RCTs. However, there is some indication of the role of the endocannabinoid system in these conditions that warrant further studies.

Mental Health screening in cystic fibrosis centres across Europe.

OBJECTIVES: The Cystic Fibrosis (CF) International Mental Health Guidelines Committee published consensus statements for screening and treating depression and anxiety in individuals with CF and their caregivers. This work aimed to evaluate the dissemination and implementation of the guidelines in Europe two years following their publication. METHODS: A 28-item survey was developed by the multidisciplinary ECFS Mental Health Working Group and emailed to approximately 300 CF centres across Europe. The survey evaluated (a) who should be responsible for mental health (MH) care, (b) the current awareness and agreement of the guidelines, (c) the provision of recommended MH screening and follow-up care, and (d) successes, barriers and required resources/training needs. RESULTS: Responses were received from 187 centres (28 countries represented). There was consensus that a psychologist should be responsible for MH care, although members of the multidisciplinary team (MDT) believed they should also share this responsibility. Sixty-two percent of respondents were aware of the guidelines; 82% percent fully, and 12% partially, agreed with them. Fifty percent (94 centres) had implemented screening. In the past year approximately 6000 patients and 2000 caregivers had been screened, with 80% of respondents using the recommended screening tools. Respondents reported 551 referrals for moderate/severe psychopathology and 84 urgent suicide ideation referrals. CONCLUSIONS: The challenges of different healthcare systems and language barriers are being overcome with a greater awareness of the importance of mental health among the MDT. MH screening is feasible and gaining momentum in both Western and Eastern Europe.

DNAAF1 links heart laterality with the AAA+ ATPase RUVBL1 and ciliary intraflagellar transport.

DNAAF1 (LRRC50) is a cytoplasmic protein required for dynein heavy chain assembly and cilia motility, and DNAAF1 mutations cause primary ciliary dyskinesia (PCD; MIM 613193). We describe four families with DNAAF1 mutations and complex congenital heart disease (CHD). In three families, all affected individuals have typical PCD phenotypes. However, an additional family demonstrates isolated CHD (heterotaxy) in two affected siblings, but no clinical evidence of PCD. We identified a homozygous DNAAF1 missense mutation, p.Leu191Phe, as causative for heterotaxy in this family. Genetic complementation in dnaaf1-null zebrafish embryos demonstrated the rescue of normal heart looping with wild-type human DNAAF1, but not the p.Leu191Phe variant, supporting the conserved pathogenicity of this DNAAF1 missense mutation. This observation points to a phenotypic continuum between CHD and PCD, providing new insights into the pathogenesis of isolated CHD. In further investigations of the function of DNAAF1 in dynein arm assembly, we identified interactions with members of a putative dynein arm assembly complex. These include the ciliary intraflagellar transport protein IFT88 and the AAA+ (ATPases Associated with various cellular Activities) family proteins RUVBL1 (Pontin) and RUVBL2 (Reptin). Co-localization studies support these findings, with the loss of RUVBL1 perturbing the co-localization of DNAAF1 with IFT88. We show that RUVBL1 orthologues have an asymmetric left-sided distribution at both the mouse embryonic node and the Kupffer's vesicle in zebrafish embryos, with the latter asymmetry dependent on DNAAF1. These results suggest that DNAAF1-RUVBL1 biochemical and genetic interactions have a novel functional role in symmetry breaking and cardiac development.

Computerized Cognitive Training in Older Adults With Mild Cognitive Impairment or Dementia: A Systematic Review and Meta-Analysis.

OBJECTIVE: Previous meta-analyses indicate that computerized cognitive training (CCT) is a safe and efficacious intervention for cognition in older adults. However, efficacy varies across populations and cognitive domains, and little is known about the efficacy of CCT in people with mild cognitive impairment or dementia. METHOD: The authors searched Medline, Embase, PsychINFO, CINAHL, and CENTRAL through July 1, 2016, for randomized controlled trials of CCT in older adults with mild cognitive impairment or dementia. Overall cognition, individual cognitive domains, psychosocial function, and activities of daily living were pooled separately for mild cognitive impairment and dementia trials. RESULTS: The overall effect on cognition in mild cognitive impairment across 17 trials was moderate (Hedges' g=0.35, 95% CI=0.20-0.51). There was no evidence of publication bias or difference between active- and passive-controlled trials. Small to moderate effects were found for global cognition, attention, working memory, learning, and memory, with the exception of nonverbal memory, and for psychosocial functioning, including depressive symptoms. In dementia, statistically significant effects were found on overall cognition (k=11, g=0.26, 95% CI=0.01-0.52) and visuospatial skills, but these were driven by three trials of virtual reality or Nintendo Wii. CONCLUSIONS: CCT is efficacious on global cognition, select cognitive domains, and psychosocial functioning in people with mild cognitive impairment. This intervention therefore warrants longer-term and larger-scale trials to examine effects on conversion to dementia. Conversely, evidence for efficacy in people with dementia is weak and limited to trials of immersive technologies.

HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome.

BACKGROUND: The genetic aetiology of neurodevelopmental defects is extremely diverse, and the lack of distinctive phenotypic features means that genetic criteria are often required for accurate diagnostic classification. We aimed to identify the causative genetic lesions in two families in which eight affected individuals displayed variable learning disability, spasticity and abnormal gait. METHODS: Autosomal recessive inheritance was suggested by consanguinity in one family and by sibling recurrences with normal parents in the second. Autozygosity mapping and exome sequencing, respectively, were used to identify the causative gene. RESULTS: In both families, biallelic loss-of-function mutations in HACE1 were identified. HACE1 is an E3 ubiquitin ligase that regulates the activity of cellular GTPases, including Rac1 and members of the Rab family. In the consanguineous family, a homozygous mutation p.R219* predicted a truncated protein entirely lacking its catalytic domain. In the other family, compound heterozygosity for nonsense mutation p.R748* and a 20-nt insertion interrupting the catalytic homologous to the E6-AP carboxyl terminus (HECT) domain was present; western blot analysis of patient cells revealed an absence of detectable HACE1 protein. CONCLUSION: HACE1 mutations underlie a new autosomal recessive neurodevelopmental disorder. Previous studies have implicated HACE1 as a tumour suppressor gene; however, since cancer predisposition was not observed either in homozygous or heterozygous mutation carriers, this concept may require re-evaluation.

An unusual phenotype of X-linked developmental delay and extreme behavioral difficulties associated with a mutation in the EBP gene.

We report on a family in which four males over three generations are affected with X-linked recessive developmental delay, learning difficulties, severe behavioral difficulties and mild dysmorphic features. Plasma sterol analysis in three of the four affected males demonstrated increased concentrations of 8-dehydrocholesterol (8-DHC) and cholest-8(9)-enol. All four affected males had a novel hemizygous missense mutation, p.W47R (c.139T>C), in EBP. Functional studies showed raised levels of cholest-8(9)-enol in patient's cultured fibroblast cells, which were suppressed when the cells were incubated with simvastatin. EBP encodes 3ß-hydroxysteroid-delta8, delta7-isomerase, a key enzyme involved in the cholesterol biosynthesis pathway. Mutations in EBP have previously been associated with Conradi-Hunermann-Happle syndrome (CHH), an X-linked dominant disorder characterized by skeletal dysplasia, skin, and ocular abnormalities, which is usually lethal in males. Four previous reports describe X-linked recessive multiple anomaly syndromes associated with non-mosaic EBP mutations in males, two at the same amino acid position, p.W47C. This phenotype has previously been described as "MEND" syndrome (male EBP disorder with neurological defects). The family reported herein represent either a novel phenotype, or an expansion of the MEND phenotype, characterized by extreme behavioral difficulties and a scarcity of structural anomalies. Simvastatin therapy is being evaluated in two males from this family.

Unraveling the genetics of Joubert and Meckel-Gruber syndromes.

Joubert (JBTS) and Meckel-Gruber (MKS) syndromes are recessive neurodevelopmental conditions caused by mutations in proteins that are structural or functional components of the primary cilium. In this review we provide an overview of their clinical diagnosis, management and molecular genetics. Both have variable phenotypes, extreme genetic heterogeneity, and display allelism both with each other and other ciliopathies. Recent advances in genetic technology have significantly improved diagnosis and clinical management of ciliopathy patients, with the delineation of some general genotype-phenotype correlations. We highlight those that are most relevant for clinical practice, including the correlation between TMEM67 mutations and the JBTS variant phenotype of COACH syndrome. The subcellular localization of the known MKS and JBTS proteins is now well-described, and we discuss some of the contemporary ideas about ciliopathy disease pathogenesis. Most JBTS and MKS proteins localize to a discrete ciliary compartment called the transition zone (TZ), and act as structural components of the so-called "ciliary gate" to regulate the ciliary trafficking of cargo proteins or lipids. Cargo proteins include enzymes and transmembrane proteins that mediate intracellular signaling. The disruption of TZ function may contribute to the ciliopathy phenotype by altering the composition of the ciliary membrane or axoneme, with impacts on essential developmental signaling including the Wnt and Shh pathways as well as the regulation of secondary messengers such as inositol-1,4,5-trisphosphate (InsP3) and cAMP. However, challenges remain in the interpretation of the pathogenic potential of genetic variants of unknown significance, and in the elucidation of the molecular mechanisms of phenotypic variability in JBTS and MKS. The further genetic and functional characterization of these conditions is essential to prioritize patients for new targeted therapies.

A mutation (L1014F) in the voltage-gated sodium channel of the grain aphid, Sitobion avenae, is associated with resistance to pyrethroid insecticides.

BACKGROUND: The grain aphid, Sitobion avenae Fabricius (Hemiptera: Aphididae), is an important pest of cereal crops. Pesticides are the main method for control but carry the risk of selecting for resistance. In response to reports of reduced efficacy of pyrethroid sprays applied to S. avenae, field samples were collected and screened for mutations in the voltage-gated sodium channel, the primary target site for pyrethroids. Aphid mobility and mortality to lambda-cyhalothrin were measured in coated glass vial bioassays. RESULTS: A single amino acid substitution (L1014F) was identified in the domain IIS6 segment of the sodium channel from the S. avenae samples exhibiting reduced pyrethroid efficacy. Bioassays on aphids heterozygous for the kdr mutation (SR) or homozygous for the wild-type allele (SS) showed that those carrying the mutation had significantly lower susceptibility to lambda-cyhalothrin. CONCLUSION: The L1014F (kdr) mutation, known to confer pyrethroid resistance in many insect pests, has been identified for the first time in S. avenae. Clonal lines heterozygous for the mutation showed 35-40-fold resistance to lambda-cyhalothrin in laboratory bioassays, consistent with the reported effect of this mutation on pyrethroid sensitivity in other aphid species.

Long-term results of screening with magnetic resonance imaging in women with BRCA mutations.

BACKGROUND: The addition of breast magnetic resonance imaging (MRI) to screening mammography for women with BRCA mutations significantly increases sensitivity, but there is little data on clinical outcomes. We report screening performance, cancer stage, distant recurrence rate, and breast cancer-specific mortality in our screening study. METHODS: From 1997 to 2009, 496 women aged 25 to 65 years with a known BRCA1/2 mutation, of whom 380 had no previous cancer history, were enrolled in a prospective screening trial that included annual MRI and mammography. RESULTS: In 1847 screening rounds, 57 cancers were identified (53 screen-detected, 1 interval, and 3 incidental at prophylactic mastectomy), of which 37 (65%) were invasive. Sensitivity of MRI vs mammography was 86% vs 19% over the entire study period (P<0.0001), but was 74% vs 35% from 1997 to 2002 (P=0.02) and 94% vs 9% from 2003 to 2009 (P<0.0001), respectively. The relative sensitivities of MRI and mammography did not differ by mutation, age, or invasive vs non-invasive disease. Of the incident cancers, 97% were Stage 0 or 1. Of 28 previously unaffected women diagnosed with invasive cancer, 1 BRCA1 mutation carrier died following relapse of a 3 cm, node-positive breast cancer diagnosed on her first screen at age 48 (annual breast cancer mortality rate=0.5%). Three patients died of other causes. None of the 24 survivors has had a distant recurrence at a median follow-up of 8.4 years since diagnosis. CONCLUSION: Magnetic resonance imaging surveillance of women with BRCA1/2 mutations will detect the majority of breast cancers at a very early stage. The absence of distant recurrences of incident cancers to date is encouraging. However, longer follow-up is needed to confirm the safety of breast surveillance.

Early maternal and neonatal morbidity associated with operative delivery in second stage of labour: a cohort study.

BACKGROUND: A frequent dilemma for obstetricians is how to keep morbidity to a minimum when faced with arrested progress at full dilatation of the cervix. Our aim was to examine maternal and neonatal morbidity associated with vaginal instrumental delivery in theatre and caesarean section, at full dilatation. METHODS: We did a prospective cohort study of 393 women, who had term, singleton, liveborn, cephalic pregnancies requiring operative delivery in theatre at full dilatation for 1 year. FINDINGS: Factors increasing the likelihood of caesarean section included maternal body-mass index greater than 30 (adjusted odds ratio 2.4, 95% CI 1.2-4.9), neonatal birthweight greater than 4.0 kg (2.3, 1.3-3.8), and occipitoposterior position (2.5, 1.6-3.9). Women undergoing caesarean section were more likely to have a major haemorrhage (>1 L; 2.8, 1.1-7.6) and extended hospital stay (>/=6 days; 3.5, 1.6-7.6) than those with vaginal delivery. Babies delivered by caesarean section were more likely to require admission for intensive care (2.6, 1.2-6.0) but less likely to have trauma (0.4, 0.2-0.7) than babies delivered by forceps. Overall neonatal morbidity was low, but a few babies in each group had serious complications (serious trauma, eight vs three; sepsis, six vs 13; and jaundice, ten vs 12 after vaginal delivery and caesarean section, respectively). Major haemorrhage was less likely after delivery by a skilled obstetrician (0.5, 0.3-0.9). INTERPRETATION: The data lend support to an aim to deliver women vaginally, unless there are clear signs of cephalopelvic disproportion, and underline the importance of skilled obstetricians supervising complex operative deliveries.

American College of Sports Medicine position stand. Exercise and type 2 diabetes.

Physical activity, including appropriate endurance and resistance training, is a major therapeutic modality for type 2 diabetes. Unfortunately, too often physical activity is an underutilized therapy. Favorable changes in glucose tolerance and insulin sensitivity usually deteriorate within 72 h of the last exercise session: consequently, regular physical activity is imperative to sustain glucose-lowering effects and improved insulin sensitivity. Individuals with type 2 diabetes should strive to achieve a minimum cumulative total of 1,000 kcal x wk(-1) from physical activities. Those with type 2 diabetes generally have a lower level of fitness (VO2max) than nondiabetic individuals. and therefore exercise intensity should be at a comfortable level (RPE 10-12) in the initial periods of training and should progress cautiously as tolerance for activity improves. Resistance training has the potential to improve muscle strength and endurance, enhance flexibility and body composition, decrease risk factors for cardiovascular disease, and result in improved glucose tolerance and insulin sensitivity. Modifications to exercise type and/or intensity may be necessary for those who have complications of diabetes. Individuals with type 2 diabetes may develop autonomic neuropathy, which affects the heart rate response to exercise, and as a result, ratings of perceived exertion rather than heart rate may need to be used for moderating intensity of physical activity. Although walking may be the most convenient low-impact mode, some persons, because of peripheral neuropathy and/or foot problems, may need to do non-weight-bearing activities. Outcome expectations may contribute significantly to motivation to begin and maintain an exercise program. Interventions designed to encourage adoption of an exercise regimen must be responsive to the individual's current stage of readiness and focus efforts on moving the individual through the various "stages of change."

Ageing of the cardiovascular system during 33 years of aerobic exercise.

BACKGROUND: increasing age affects aerobic capacity, with an average loss of 10% or more per decade. AIM: to determine the effect of ageing on the circulatory system in middle-aged men during 33 years of physical training. METHODS: 15 men initially aged 45 years took part in an exercise training programme for 25-33 years. Nine serial measurements were made at rest and during maximal effort. Aerobic training consisted of swimming, jogging, walking and cycling 3-4 times per week. Sessions were for 61-70 min at 77-84% of heart rate reserve. RESULTS: there was no change in resting heart rate, blood pressure, percentage fat or body composition. Minimal cardiovascular losses at maximal work included 5.8-6.8% in maximal oxygen uptake per decade, 25 beats in maximum heart rate and 26 beats in heart rate reserve. CONCLUSION: exercise training has a favourable effect on ageing of the cardiovascular system in older men, resulting in minimal loss of oxygen uptake, no rise in resting blood pressure and no change in body composition.