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The genome sequence of the leafhopper, Arthaldeus pascuellus (Fallén, 1826) (Hemiptera: Cicadellidae) [version 1; peer review: 2 approved]
Get PDFHuman‐derived cardiac‐neural microtissues reveal catecholaminergic polymorphic ventricular tachycardia is also a disease of the sympathetic neuron
Get PDFSudden cardiac death in young individuals with structurally normal hearts represents a critical unresolved clinical challenge and typically occurs in patients with inherited arrhythmia syndromes due to cardiac channelopathies. Catecholaminergic polymorphic ventricular tachycardia (CPVT) can cause fatal arrhythmias triggered by adrenergic stimulation. Therapeutic interventions primarily target cardiac myocytes (CMs) despite robust clinical evidence demonstrating the life‐saving efficacy of cardiac sympathetic denervation. To understand this therapeutic paradox, we developed human induced pluripotent stem cell (hiPSC)‐derived CMs and sympathetic neurons (SNs) from healthy individuals and CPVT patients to investigate neurocardiac interactions using two‐ and three‐dimensional microtissue models. We tested the hypothesis that CPVT is also a disease of the autonomic nervous system and observed that CPVT hiPSC‐derived SNs had enhanced calcium transients, elevated cyclic adenosine monophosphate levels, and hyperexcitability, similar to diseased cardiomyocytes. Critically, co‐culturing diseased neurons with healthy CMs induced arrhythmogenic activity, establishing that neuronal dysfunction directly triggers cardiac arrhythmias. Multielectrode array recordings, optical mapping and single‐cell RNA sequencing revealed dysregulated neurotransmitter pathways and identified druggable molecular targets within SNs. These findings may explain why surgically interrupting sympathetic nerves helps CPVT patients and identify the nervous system as a therapeutic target. They further suggest that CPVT is more than a disease of the CM and should be re‐defined as a neuro‐cardiac disorder that paves the way for neuromodulation therapy. image Key points: Sympathetic nerve overactivity is pro‐arrhythmic and a key contributor to ventricular tachycardia and sudden cardiac death in patients with cardiac channelopathies. Catecholaminergic polymorphic ventricular tachycardia (CPVT) sympathetic neurons (SNs) exhibit enhanced calcium transients, elevated cAMP levels, and hyperexcitability that directly trigger arrhythmias in healthy cardiomyocytes. Novel human induced pluripotent stem cell‐derived cardiac‐neural microtissue models reveal CPVT is also a neurological disorder involving dysfunctional neurocardiac interactions. Single‐cell RNA sequencing identifies dysregulated neurotransmitter pathways in SNs, providing new therapeutic targets for neuromodulation therapy
Ecological harshness has a weak influence on reproductive trade-offs in a great tit population
Get PDFLack’s seminal work on bird clutch sizes has spurred expansive research on reproductive trade-offs, especially focusing on offspring quantity–quality trade-offs and the potential fitness consequences for the parents. The environment is a critical driver of the expression of individual reproductive traits, influencing them through plastic responses. However, the plasticity of reproductive trade-offs themselves across environments has seldom been studied, and these studies were often limited to experimental approaches and dichotomous environments. Using 58 years of detailed data from a great tit population, we employ the recently developed ‘covariance reaction norm’ (CRN) model to explore how continuous environmental variation influences the shape of reproductive trade-offs among individuals. Our analysis reveals that the correlation potentially indicative of the offspring quantity–quality trade-off is predominantly stable across years, with minimal variation linked to ecological harshness during the breeding season. However, the CRN also demonstrated that, despite some uncertainty associated with the results, the correlation between offspring mass and future offspring recruitment was positive, but only under harsh environmental conditions, suggesting that producing larger offspring provides fitness benefits when breeding conditions are suboptimal, which may reflect the importance of size for early-life competition. Altogether, this work highlights that there is temporal variation in some of the phenotypic correlations. This is a consequence of variation in offspring investment across breeding seasons, which is mostly driven by environmental conditions. Our study shows the benefits of exploring old ecological questions in the light of new statistical methods, highlighting the importance of understanding how environmental variation shapes the expression of life history trade-offs and the evolution of plasticity in reproductive strategies
ATRX loss couples genome instability at a G-rich repeat to dysregulation of human alpha-globin expression
Get PDFGermline mutations in the chromatin remodelling protein ATRX cause a severe developmental disorder associated with α-thalassemia. In addition, ATRX is amongst the twenty genes most frequently mutated in cancer. How ATRX mutations alter gene expression remains unclear. Using the α-globin locus as a model, here we show that ATRX deficiency downregulates α-globin in a subset of cells exhibiting DNA damage. A G-rich repeat at the α-globin locus serves as a potential site of G-quadruplex formation and DNA damage. ATRX binds this repeat co-transcriptionally, and its loss increases R-loop accumulation at this site, leading to local DNA damage and transcriptional disruption in cis. Deletion of this repeat abolishes this effect, while targeted DNA damage reinstates it. These findings reveal a mechanism linking ATRX's role in genome stability to transcriptional regulation and uncover a molecular basis of human genetic disease mediated via a distal G-rich repeat
A further novel species of Macrobrachium from Brazil (Decapoda, Palaemonidae), lacking a mandibular palp
No full textA new species of Macrobrachium from the Paraguay River basin, Brazil, is described. The new species is distinguished from most of its congeners by the absence of a mandibular palp. Morphologically, the new species is similar to M. bouvieri (Sollaud, 1911), with the presence of a postorbital rostral tooth, a straight rostrum, and the presence of a double row of setae without gaps over the teeth along the ventral margin of rostrum, separating it from that species, as well as the other eight species of Macrobrachium lacking a mandibular palp
Training health professionals in smoking cessation
Get PDFRationale
Cigarette smoking is one of the leading causes of preventable death worldwide. There is good evidence that brief interventions by health professionals can increase smoking cessation attempts. However, as new studies become available, the effectiveness of these training programmes needs to be re‐assessed to inform public policy, clinical care, and guideline recommendations. This is an update of a Cochrane review first published in 2000, and previously updated in 2012.
Objectives
To assess the effectiveness of training healthcare professionals to deliver smoking cessation interventions to their patients, and to assess the effects of training characteristics (such as content, setting, delivery, and intensity).
Search methods
We searched the following databases from inception to August 2024: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; PsycINFO; ClinicalTrials.gov (through CENTRAL); and the World Health Organization International Clinical Trials Registry Platform (through CENTRAL). We also searched the references of eligible studies.
Eligibility criteria
We included randomised trials in which the intervention was training of healthcare professionals in smoking cessation. We considered trials for inclusion if they reported outcomes for patient smoking at least six months after the intervention. Process outcomes needed to be reported. However, we excluded trials that reported effects only on process outcomes and not smoking behaviour.
Outcomes
The critical outcome measure was abstinence from smoking six months or more after baseline, using the strictest measure of abstinence available at the longest follow‐up. Prolonged or continuous abstinence was preferred over point prevalence. Our important outcome was the number of participants who made a quit attempt.
Risk of bias
Working independently, two review authors evaluated the risk of bias using the Cochrane RoB 1 tool, following guidance from the Cochrane Tobacco Addiction Group.
Synthesis methods
Working independently, two review authors extracted information about the characteristics of each included study (i.e. interventions, participants, outcomes, and methods). We pooled studies using random‐effects meta‐analysis where possible and otherwise summarised findings using narrative synthesis in text and tables. We used the GRADE framework to assess the certainty of the evidence.
Included studies
We included 29 studies in the review, published between 1989 and 2024. Together, the studies provided training for over 4030 health professionals, and data for 38,178 participants. We assessed 10 studies to have an overall low risk of bias, 17 an unclear risk, and two to have an overall high risk of bias.
Synthesis of results
Sixteen studies compared training of healthcare professionals in smoking cessation to no training, and assessed the effect on the number of participants abstinent at longest follow‐up. High‐certainty evidence indicates that smoking cessation training for healthcare professionals increases patient smoking cessation compared with no training (risk ratio (RR) 1.34, 95% confidence interval (CI) 1.08 to 1.67; I2 = 48%; 16 studies, 16,513 participants). We conducted three subgroup analyses to test the effect of specific potential sources of heterogeneity: training intensity, type of healthcare professional trained, and treatment recommended in the training; none found evidence of between‐group heterogeneity.
Four studies assessed the effect of high‐intensity training for healthcare professionals on the number of participants abstinent at longest follow‐up compared with lower‐intensity training. The evidence suggests that higher‐intensity training may increase smoking cessation compared with lower‐intensity training, though confidence intervals were wide and included the potential for no benefit (RR 1.64, 95% CI 0.86 to 3.12; I2 = 54%; 4 studies, 1151 participants; low‐certainty evidence).
Three studies assessed the impact of adjuncts to training on the number of participants abstinent at longest follow‐up. We found low‐certainty evidence that when the healthcare professionals treating them are trained in smoking cessation, more people may quit when also provided with nicotine replacement therapy (RR 1.64, 95% CI 0.72 to 3.71; I2 = 69%; 2 studies, 1892 participants), and very low‐certainty evidence that providing prompts to healthcare professionals in addition to smoking cessation training may help more people to quit (RR 1.37, 95% CI 0.69 to 2.70; I2 = 66%; 3 studies, 2429 participants). However, in both cases, confidence intervals were wide and included the potential for no benefit.
Authors' conclusions
High‐certainty evidence supports the effectiveness of training health professionals in smoking cessation when compared with no training. Multi‐component investigations incorporating new pharmacological interventions for smoking cessation (such as varenicline and bupropion) or other cessation aids alongside physician training should be considered to determine if any additional benefit in long‐term abstinence can be obtained.
Funding
Production of this review was supported by PhD scholarship funding from the University of Adelaide and co‐funded by Houd Research Group, awarded to KS.
Registration
This review was first published outside of Cochrane in 1994 and subsequently updated as a Cochrane review in 2000 (DOI: 10.1002/14651858.CD000214) and 2012 (DOI: 10.1002/14651858.CD000214.pub2). No protocol was published or registered
Casimir energy stabilization of Standard Model landscape in dark dimension
Get PDFIn this paper we present a realization of the dark dimension. We consider the 5D Standard Model coupling to gravity with one dimension compactified on an orbifold, which is seen as the dark dimension of size R. We stabilize the radion by Casimir effect wrapping around the compact dimension and recover the neutrino mass and 4D cosmological constant with the observed value. Orbifold can lead to a natural resolution of chirality problem in 5D at low energy, which we briefly discussed in the paper. Although we found that the radion mass is too light to survive under solar system tests of GR, several screening mechanisms might give us a solution, for example, the Chameleon mechanism
Structural basis for recognition of Rift Valley fever virus Gn protein by a human neutralizing monoclonal antibody with a kappa light chain
Get PDFRift Valley fever virus (RVFV) poses a continued threat to human health and animal husbandry. Two neutralizing and protective human monoclonal antibodies (mAbs), RVFV-268 and RVFV-379, exhibit similar affinities and epitope footprints on the Gn glycoprotein component of the RVFV Gn-Gc capsomeric lattice. Here, we define fine details of the biophysical determinants of Gn recognition used by RVFV human monoclonal antibodies through studying an antibody encoded by a set of recombined genes not previously identified in RVFV antibodies. We find that RVFV-379 exhibits a larger footprint than that observed for RVFV-268 and other antibodies targeting the same region, which involves major contributions of both the light and heavy chains. RVFV-379 also uses an oblique angle of approach towards the virion surface that contrasts with the perpendicular angle of engagement observed for some other potently neutralizing human mAbs. Further, consistent with amino acid sequence variation within and proximal to the RVFV-379 epitope, in vitro neutralization screening reveals a limited degree of neutralization breadth across prevalent RVFV strains, suggesting that RVFV has fewer functional constraints at this region of the virus envelope. By dissecting the molecular determinants of mAb recognition of Gn, this integrated analysis refines strategies needed for the rational design of vaccines that can elicit a potent and species-wide protective antibody immune response to this important re-emerging pathogen
Spatiotemporal patterns of marine biodiversity through the Phanerozoic
Get PDFThe fossil record offers direct evidence of how life navigates major environmental upheavals, providing a critical framework for anticipating extinction risk in the face of accelerating anthropogenic climate change. Drawing on global marine invertebrate data across the Phanerozoic, this thesis shows that extinction risk is governed by the complex interplay of biological traits, paleogeographic constraints, and especially the magnitude of climate change. Traits such as broad geographic range and physiological tolerance mediate risk during stable intervals, yet even the most resilient taxa can be overwhelmed when climate shifts are sufficiently extreme. Quantitative analyses reveal that paleogeographic boundary conditions, most notably coastline geometry, nonrandomly shape extinction during mass extinctions and hyperthermals, challenging classic paradigms of extinction as purely stochastic. Finally, the inconsistent coupling of realized niches to environmental change over time highlights the complex idiosyncratic response of surviving taxa to climate change. Together, these findings highlight the power of paleontological frameworks to identify which species and settings were most vulnerable to climate change in the past and will be prone to extinction as climate change intensifies
Current rehabilitation for adults with peripheral nerve injuries in the UK: An online survey
Get PDFIntroductionPeripheral nerve injuries can lead to paralysis, sensory loss, chronic pain, and profound psychological and vocational consequences. Recent UK guidelines recommend biopsychosocial rehabilitation, yet qualitative evidence suggest gaps in service provision. This study explored current rehabilitation and perceived barriers among therapists treating adults with peripheral nerve injuries.MethodsA cross-sectional online survey was distributed to UK physiotherapists and occupational therapists experienced in upper and lower limb peripheral nerve injury rehabilitation. Questions captured demographics, treatment strategies before and after reinnervation, access to psychological support, and perceived organisational barriers. Descriptive analysis was undertaken.ResultsFifty-three respondents (60% physiotherapists, 40% occupational therapists) completed the survey; 70% had more than 10 years' experience. Ninety eight percent of respondents treated adults with upper limb nerve injuries. Motor and sensory interventions (active and passive range of motion, splinting, strength training, and functional activity) were reported as "always/frequently" used by >80% of respondents. Over a quarter of respondents (28%) occasionally/rarely used pain neuroscience education. Other specific psychological interventions including cognitive behavioural techniques and mindfulness were rarely used (ConclusionsUK rehabilitation for adults with peripheral nerve injuries remains predominantly biomedical, with limited integration of psychologically informed care and limited access to Clinical Psychology. Addressing systemic barriers and evaluating digital or hybrid models may enable more biopsychosocial, patient-centred care