Activin type I receptor polymorphisms and body composition in older individuals with sarcopenia-Analyses from the LACE randomised controlled trial.

BACKGROUND: Ageing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia. METHODS: We compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial. RESULTS: Neither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone. CONCLUSION: These data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals.

The validity of Engagement and Feedback Assessments (EFAs): identifying students at risk of failing.

BACKGROUND: Imperial College School of Medicine, London UK, introduced a new curriculum in 2019, with a focus on the GMC outcomes for graduates, and pedagogy best practice. The new curriculum included formative assessments, named engagement and feedback assessments (EFAs), to support learning, and attainment in the summative examinations. The aims of this study were to assess the validity of EFAs and to determine whether they have utility as a modified form of programmatic assessment to inform decision-making regarding possible interventions by measuring and analysing attendance at and performance in these formative events. METHODS: Seven hundred and sixty-one students were included in the study and assessment results were included for academic years 2019/20 to 2020/21. Forty-one data points per student, (27 in Year 1 and 14 in Year 2) were used, to compare EFA scores with the summative performance. Attendance was monitored through engagement with the EFAs. RESULTS: Cohort 1 (enrolled 2019): In year 1, EFAs were associated with summative exam scores (overall r = 0.63, p < 0.001). Year 2, EFA scores were also associated with summative scores (overall r = 0.57, p < 0.001), including the clinical practical assessment (r = 0.45, p < 0.001). Missing two or more EFAs was associated with a significant increase in the likelihood of failing one or more summative examinations in the first year (OR: 7.97, 95% CI 2.65-34.39) and second year (OR: 3.20, 95% CI 1.74-5.95). Missing more than two EFAs in their first year was also associated with a higher risk of failing a summative examination in the second year (OR: 2.47, 95% CI 1.33-4.71). Students who increased their attendance between year 1 and 2 fared better in summative assessment than those who maintained poor attendance, whereas those that reduced their attendance fared worse than those that maintained high attendance. Cohort 2 (enrolled 2020): Analysis of cohort 2 supported these findings and in this cohort missing two or more EFAs was again associated with an increased likelihood of failing a summative examination (OR = 4.00, 95% CI = 2.02-7.90). CONCLUSION: Our EFA model has validity in predicting performance in summative assessments and can inform prospective interventions to support students' learning. Enhancing attendance and engagement can improve outcomes.

ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial.

BACKGROUND: Angiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study. METHODS: Sarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months' treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables. RESULTS: Allele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo. CONCLUSION: Our results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype.

Over 200,000 kilometers of free-flowing river habitat in Europe is altered due to impoundments.

European rivers are disconnected by more than one million man-made barriers that physically limit aquatic species migration and contribute to modification of freshwater habitats. Here, a Conceptual Habitat Alteration Model for Ponding is developed to aid in evaluating the effects of impoundments on fish habitats. Fish communities present in rivers with low human impact and their broad environmental settings enable classification of European rivers into 15 macrohabitat types. These classifications, together with the estimated fish sensitivity to alteration of their habitat are used for assessing the impacts of six main barrier types (dams, weirs, sluices, culverts, fords, and ramps). Our results indicate that over 200,000 km or 10% of previously free-flowing river habitat has been altered due to impoundments. Although they appear less frequently, dams, weirs and sluices cause much more habitat alteration than the other types. Their impact is regionally diverse, which is a function of barrier height, type and density, as well as biogeographical location. This work allows us to foresee what potential environmental gain or loss can be expected with planned barrier management actions in rivers, and to prioritize management actions.

The influence of flow velocity on the response of rheophilic fish to visual cues.

The strong association with visual cues exhibited by fish that prefer to inhabit flowing water (rheophilic species) may help reduce the energetic costs of maintaining position due to the provision of spatial points of reference. If this "Station Holding Hypothesis" is true, a positive relationship between the association with visual cues and flow velocity is expected. This hypothesis was tested experimentally by quantifying the response of common minnow (Phoxinus phoxinus) and brown trout (Salmo trutta) to visual cues under three flow velocities. In contradiction to the prediction, there was no evidence that the association with strong visual cues was positively related to flow velocity when fish were presented with vertical black stripes in an open channel flume, although interspecific variation in response was observed. The association with visual cues was relatively weak in trout, compared to minnow that spent 660% more time associated with the zone in which visual cues were present during the treatment, than the control when visual cues were absent. Trout tended to be more exploratory and made short visits to the area where visual cues were present, whereas minnow associated with the cues for longer. The strong association with visual cues independent of flow velocity exhibited by minnow and the weak association across all velocities by trout suggest that this behaviour is unlikely to reflect a strategy to minimise the energetic cost of maintaining position in flowing water. Minnow may have used the visual cues as a proxy indicator of physical structure that provides alternative benefits, such as refuge from predators. Trout may have employed alternative cues (e.g. mechanosensory) to seek more energetically favourable regions of the experimental area, reducing the importance of stationary visual stimuli.

Acute Sarcopenia after Elective and Emergency Surgery.

Sarcopenia is an increasingly recognised condition of loss of muscle mass and function. The European Working Group on Sarcopenia in Older People 2 (EWSOP2) updated their definition in 2018, emphasising the importance of low muscle strength in diagnosis. Acute sarcopenia has been arbitrarily defined as sarcopenia lasting less than 6 months. This review highlights the pathophysiology involved in muscle wasting following surgery, focussing on hormonal factors, inflammation, microRNAs, and oxidative stress. Biomarkers such as GDF-15, IGF-1 and various microRNAs may predict post-surgical muscle loss. The impact of existing sarcopenia on various types of surgery and incident muscle wasting following surgery is also described. The gaps in research found include the need for longitudinal studies looking in changes in muscle strength and quantity following surgery. Further work is needed to examine if biomarkers are replicated in other surgery to consolidate existing theories on the pathophysiology of muscle wasting.

Response of upstream migrating juvenile European eel (Anguilla anguilla) to electric fields: Application of the marginal gains concept to fish screening.

The decline in European eel (Anguilla anguilla) recruitment over the past half-century is partly due to river infrastructure that delays or blocks upstream migration to rearing habitat. Stimuli, such as electricity, can be used to modify the behaviour of downstream moving fish and guide them to preferred routes of passage at river infrastructure; but research on upstream migrating juvenile eel remains limited. The response of upstream migrating juvenile eel exposed to pulsed direct current (PDC) electric fields was investigated using a recirculatory flume. Eel were presented a choice of two routes upstream under either: (1) a treatment condition, in which the selection of one route resulted in exposure to High Electric Field (HEF) strength that was between 1.5-2 times stronger than the Low Electric Field (LEF) strength encountered in the alternative route; or (2) a control in which the electric field was absent in both routes. Under the treatment, five different mean HEF strengths (0.53, 0.77, 1.22, 2.17 and 3.74 Vcm-1) were tested at one of two frequencies (2 and 10 Hz). Route choice, distance downstream of the first set of electrodes at which an initial response was observed and avoidance behaviours (acceleration, retraction, switching and rejection) were compared among treatments. For the 1.22, 2.17 and 3.74 Vcm-1 and under 2 Hz, eel preferred to pass the LEF route. Avoidance was greater in the HEF route and positively related to field strength. The distance of the initial response did not differ between routes, field strengths or frequency. Upstream migrating eel avoided electric fields indicating potential to develop this approach for fish guidance. Further work is needed to test prototypes in field settings, particularly in combination with traditional physical screens to water intakes as part of a process of applying the concept of marginal gains to advance environmental impact mitigation technology.

Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial.

BACKGROUND: This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia. METHODS: Placebo-controlled, parallel group, double-blind, randomized two-by-two factorial trial. We recruited adults aged ≥ 70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4 m walk) and/or low handgrip strength (women < 20 kg, men < 30 kg) plus low muscle mass (using sex and body mass index category-specific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomized to perindopril 4 mg or placebo, and to oral leucine powder 2.5 g or placebo thrice daily. The primary outcome was the between-group difference in the short physical performance battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy. RESULTS: We screened 320 people and randomized 145 participants compared with an original target of 440 participants. For perindopril [n = 73, mean age 79 (SD 6), female sex 39 (53%), mean SPPB 7.1 (SD 2.3)] versus no perindopril [n = 72, mean age 79 (SD 6), female sex 39 (54%), mean SPPB 6.9 (SD 2.4)], median adherence to perindopril was lower (76% vs. 96%; P < 0.001). Perindopril did not improve the primary outcome [adjusted treatment effect -0.1 points (95%CI -1.2 to 1.0), P = 0.89]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.4 kg (95%CI -1.1 to 0.3), P = 0.27]. More adverse events occurred in the perindopril group (218 vs. 165), but falls rates were similar. For leucine [n = 72, mean age 78 (SD 6), female sex 38 (53%), mean SPPB 7.0 (SD 2.1)] versus no leucine [n = 72, mean age 79 (SD 6), female sex 40 (55%), mean SPPB 7.0 (SD 2.5)], median adherence was the same in both groups (76% vs. 76%; P = 0.99). Leucine did not improve the primary outcome [adjusted treatment effect 0.1 point (95%CI -1.0 to 1.1), P = 0.90]. No significant treatment benefit was seen for any secondary outcome including muscle mass [adjusted treatment effect -0.3 kg (95%CI -1.0 to 0.4), P = 0.47]. Meta-analysis of angiotensin converting enzyme inhibitor/angiotensin receptor blocker trials showed no clinically important treatment effect for the SPPB [between-group difference -0.1 points (95%CI -0.4 to 0.2)]. CONCLUSIONS: Neither perindopril nor leucine improved physical performance or muscle mass in this trial; meta-analysis did not find evidence of efficacy of either ACE inhibitors or leucine as treatments to improve physical performance.

Bisphenol A and its alternatives in Austrian thermal paper receipts, and the migration from reusable plastic drinking bottles into water and artificial saliva using UHPLC-MS/MS.

Bisphenol A (BPA) a synthetic, high production volume chemical identified as endocrine disruptor and toxic to reproduction is mainly used in the production of polycarbonate plastics, in epoxy resins, polyvinylchloride, thermal papers as color developer, and is present in a wide range of consumer goods such as food packaging materials, storage containers, and cash receipts. Due to its effects on health and legal restrictions, BPA is increasingly replaced by other bisphenols. In this study, BPA and 13 alternatives including BPS, Bisphenol F (BPF), Bisphenol B (BPB), Bisphenol C (BPC), Bisphenol Z (BPZ), Bisphenol M (BPM), Bisphenol P (BPP), Bisphenol AF (BPAF), Bisphenol FL (BPFL), Bisphenol C12 (BPC12), Tetramethylbisphenol A (tmBPA), 4,4-bisphenol (BP-4,4), and p,p-oxybisphenol were analyzed in thermal paper cash receipts (content) and migration studies were carried out in BPA-free labelled reusable plastic drinking bottles using a sensitive UHPLC-MS/MS method. The receipts contained almost only BPA and BPS, whereas BPS was found in all samples ranging at levels up to 38 µg/g. BPA was detected at low concentrations, only in one sample 11,000 µg/g were found, exceeding the EU limit of BPA in thermal paper of 0.02% per weight. In leaching solutions from the drinking bottles BPA, BPS and BPF were found at concentrations up to 0.047 µg/L BPA, 0.043 µg/L BPS, and <0.01 µg/L BPF. No other analogues were detected. However, these levels identified are far below the legal limits. In addition, a theoretical exposure assessment was conducted indicating that exposures were within the current regulatory guidelines.

The response of common carp (Cyprinus carpio) to insonified bubble curtains.

Acoustic bubble curtains have been marketed as relatively low cost and easily maintained behavioural deterrents for fisheries management. Their energy efficiency can be improved by reducing air flow and exploiting bubble resonance. In a series of three flume experiments, we: (1) investigated the reactions of carp to a low air flow bubble curtain, (2) compared the effectiveness of resonant versus non-resonant insonified bubble curtains (for the same volume flux of gas injected through the nozzles) to deter passage, and determined the stimuli responsible for eliciting deterrence, and (3) included the effect of visual cues generated by the bubble curtain. This study showed that bubble curtains with a higher proportion of resonant bubbles deterred carp relatively better. Passage rejection was likely influenced by multiple cues at distances within a body length of the fish- specifically the rate of change in both particle motion and flow velocity caused by rising bubbles. All acoustic bubble curtains were less effective in the presence of daylight, suggesting that vision plays an important role at mediating carp reactions. We discuss the importance of ascertaining the bubble size distribution, in addition to the gas flow rate and aperture size, when characterising acoustically active bubble curtains.

Prevalence and treatment implications of ICD-11 complex PTSD in Australian treatment-seeking current and ex-serving military members.

Background: Despite growing support for the distinction between posttraumatic stress disorder (PTSD) and complex PTSD (CPTSD) as separate diagnoses within the ICD-11 psychiatric taxonomy, the prevalence and treatment implications of CPTSD among current and ex-serving military members have not been established. Objective: The study aims were to a) establish the prevalence of provisional ICD-11 CPTSD diagnosis relative to PTSD in an Australian sample of treatment-seeking current and ex-serving military members, and b) examine the implications of CPTSD diagnosis for intake profile and treatment response. Methods: The study analysed data collected routinely from Australian-accredited treatment programmes for military-related PTSD. Participants were 480 current and ex-serving military members in this programmes who received a provisional ICD-11 diagnosis of PTSD or CPTSD at intake using proxy measures. Measures of PTSD symptoms, disturbances in self-organisation, psychological distress, mental health and social relationships were considered at treatment intake, discharge, and 3-month follow-up. Results: Among participants with a provisional ICD-11 diagnosis, 78.2% were classified as having CPTSD, while 21.8% were classified as having PTSD. When compared to ICD-11 PTSD, participants with CPTSD reported greater symptom severity and psychological distress at intake, and lower scores on relationship and mental health dimensions of the quality of life measure. These relative differences persisted at each post-treatment assessment. Decreases in PTSD symptoms between intake and discharge were similar across PTSD (d RM  = -0.81) and CPTSD (d RM  = -0.76) groups, and there were no significant post-treatment differences between groups when controlling for initial scores. Conclusions: CPTSD is common among treatment-seeking current and ex-serving military members, and is associated with initially higher levels of psychiatric severity, which persist over time. Participants with CPTSD were equally responsive to PTSD treatment; however, the tendency for those with CPTSD to remain highly symptomatic post-treatment suggests additional treatment components should be considered.

Antecedentes: A pesar del creciente apoyo para la distinción entre trastorno de estrés postraumático (TEPT) y trastorno de estrés postraumático complejo (TEPTC) como diagnósticos separados dentro de la taxonomía psiquiátrica de la CIE-11, la prevalencia y las implicaciones en el tratamiento del TEPTC dentro de miembros militares activos o en retiro no han sido establecidas.Objetivo: Los objetivos del estudio fueron a) establecer la prevalencia de TEPTC provisional según CIE-11 en relación al TEPT en una muestra australiana de miembros militares activos o en retiro en busca de tratamiento, y b) examinar las implicaciones del diagnóstico de TEPTC para el perfil de ingreso y respuesta a tratamiento.Método: El estudio analizó datos recolectados de forma rutinaria por programas de tratamiento australianos acreditados para TEPT relacionado a militares. Los participantes fueron 480 miembros activos o en retiro ingresados a este programa bajo el diagnóstico provisional de TEPT o TEPTC según CIE-11 a través de indicadores indirectos. Al ingreso, egreso y a los 3 meses de seguimiento, se consideraron mediciones de los síntomas de TEPT, alteraciones en la organización del Yo, estrés psicológico, salud mental y relaciones sociales.Resultados: Dentro de los participantes con un diagnóstico provisional según CIE-11, el 78,2% fue clasificado como portador de TEPTC, mientras que un 21,8% fue clasificado como portador de TEPT. Al ser comparados con TEPT según CIE-11, los participantes con TEPTC reportaron al ingreso una mayor severidad en la sintomatología y en el estrés psicológico, y menores puntajes en las dimensiones de medida de calidad de vida de salud mental y relaciones sociales. Estas diferencias relativas persistieron en cada seguimiento posterior al tratamiento. Las disminuciones en los síntomas de TEPT entre el ingreso y el egreso fueron similares entre los grupos con TEPT (d RM = -0.81) y TEPTC (d RM = -0.76), y no hubo diferencias significativas post-tratamiento entre los grupos al controlarlos según los puntajes iniciales. Conclusiones: El TEPTC es común dentro de miembros militares activos o en retiro en busca de tratamiento, y está asociado a mayores niveles de severidad psiquiátrica inicial, la cual persiste a lo largo del tiempo. Los participantes con TEPTC respondieron igualmente al tratamiento del TEPT; sin embargo, la tendencia de aquéllos con TEPTC de permanecer altamente sintomáticos tras el tratamiento sugiere componentes de tratamiento adicionales que deberían ser considerados.

Collective behaviour of the European minnow (Phoxinus phoxinus) is influenced by signals of differing acoustic complexity.

Collective behaviour, such as shoaling in fish, benefits individuals through a variety of activities such as social information exchange and anti-predator defence. Human driven disturbance (e.g. anthropogenic noise) is known to affect the behaviour and physiology of individual animals, but the disruption of social aggregations of fish remains poorly understood. Anthropogenic noise originates from a variety of activities and differs in acoustic structure, dominant frequencies, and spectral complexity. The response of groups of fish may differ greatly, depending on the type of noise, and how it is perceived (e.g. threatening or attractive). In a controlled laboratory study, high resolution video tracking in combination with fine scale acoustic mapping was used to investigate the response of groups of European minnows (Phoxinus phoxinus) to signals of differing acoustic complexity (sinewave tones vs octave band noise) under low (150 Hz) and high (2200 Hz) frequencies. Fish startled and decreased their mean group swimming speed under all four treatments, with low frequency sinewave tones having the greatest influence on group behaviour. The shoals exhibited spatial avoidance during both low frequency treatments, with more time spent in areas of lower acoustic intensity than expected. This study illustrates how noise can influence the spatial distribution and social dynamics within groups of fish, and owing to the high potential for freshwater aquatic environments to be influenced by anthropogenic activity, wider consequences for populations should be further investigated.

Artificial light at night (ALAN) affects the downstream movement behaviour of the critically endangered European eel, Anguilla anguilla.

Artificial light at night (ALAN) is considered one of the most pervasive forms of environmental pollution. It is an emerging threat to freshwater biodiversity and can influence ecologically important behaviours of fish. The European eel (Anguilla anguilla) is a critically endangered catadromous species that migrates downstream to the ocean to spawn in the Sargasso Sea. Given the pervasive nature of ALAN, many eel will navigate through artificially lit routes during their seaward migration, and although considered negatively phototactic, their response has yet to be quantified. We investigated the response of downstream moving European eel to simulated ALAN using a Light Emitting Diode unit in an experimental flume. We presented two routes of passage under: (1) a dark control (both channels unlit), (2) low ALAN (treatment channel lit to ca. 5 lx), or (3) high ALAN (treatment channel lit to ca. 20 lx). Eel were: (i) more likely to reject an illuminated route when exposed to high levels of ALAN; (ii) less likely to select the illuminated channel when given a choice; and (iii) passed downstream more rapidly when the illuminated route was selected. This study quantified the response of the critically endangered European eel to ALAN under an experimental setting, providing the foundations for future field based research to validate these findings, and offering insight on the ecological impacts of this major environmental pollutant and driver of global change.

Characterization of Negative Allosteric Modulators of the Calcium-Sensing Receptor for Repurposing as a Treatment of Asthma.

Asthma is still an incurable disease, and there is a recognized need for novel small-molecule therapies for people with asthma, especially those poorly controlled by current treatments. We previously demonstrated that calcium-sensing receptor (CaSR) negative allosteric modulators (NAMs), calcilytics, uniquely suppress both airway hyperresponsiveness (AHR) and inflammation in human cells and murine asthma surrogates. Here we assess the feasibility of repurposing four CaSR NAMs, which were originally developed for oral therapy for osteoporosis and previously tested in the clinic as a novel, single, and comprehensive topical antiasthma therapy. We address the hypotheses, using murine asthma surrogates, that topically delivered CaSR NAMs 1) abolish AHR; 2) are unlikely to cause unwanted systemic effects; 3) are suitable for topical application; and 4) inhibit airway inflammation to the same degree as the current standard of care, inhaled corticosteroids, and, furthermore, inhibit airway remodeling. All four CaSR NAMs inhibited poly-L-arginine-induced AHR in naïve mice and suppressed both AHR and airway inflammation in a murine surrogate of acute asthma, confirming class specificity. Repeated exposure to inhaled CaSR NAMs did not alter blood pressure, heart rate, or serum calcium concentrations. Optimal candidates for repurposing were identified based on anti-AHR/inflammatory activities, pharmacokinetics/pharmacodynamics, formulation, and micronization studies. Whereas both inhaled CaSR NAMs and inhaled corticosteroids reduced airways inflammation, only the former prevented goblet cell hyperplasia in a chronic asthma model. We conclude that inhaled CaSR NAMs are likely a single, safe, and effective topical therapy for human asthma, abolishing AHR, suppressing airways inflammation, and abrogating some features of airway remodeling. SIGNIFICANCE STATEMENT: Calcium-sensing receptor (CaSR) negative allosteric modulators (NAMs) reduce airway smooth muscle hyperresponsiveness, reverse airway inflammation as efficiently as topical corticosteroids, and suppress airway remodeling in asthma surrogates. CaSR NAMs, which were initially developed for oral therapy of osteoporosis proved inefficacious for this indication despite being safe and well tolerated. Here we show that structurally unrelated CaSR NAMs are suitable for inhaled delivery and represent a one-stop, steroid-free approach to asthma control and prophylaxis.

Induced pluripotent stem cells derived from the developing striatum as a potential donor source for cell replacement therapy for Huntington disease.

BACKGROUND: Cell replacement therapy (CRT) for Huntington disease (HD) requires a source of striatal (STR) progenitors capable of restoring the function lost due to STR degeneration. Authentic STR progenitors can be collected from the fetal putative striatum, or whole ganglionic eminence (WGE), but these tissues remain impractical for widespread clinical application, and alternative donor sources are required. Here we begin exploring the possibility that induced pluripotent stem cells (iPSC) derived from WGE may retain an epigenetic memory of their tissue of origin, which could enhance their ability to differentiate into STR cells. RESULTS: We generate four iPSC lines from human WGE (hWGE) and establish that they have a capacity similar to human embryonic stem cells with regard to their ability to differentiate toward an STR phenotype, as measured by expression and demethylation of key STR genes, while maintaining an overall different methylome. Finally, we demonstrate that these STR-differentiated hWGE iPSCs share characteristics with hWGE (i.e., authentic STR tissues) both in vitro and following transplantation into an HD model. Overall, iPSCs derived from human WGE show promise as a donor source for CRT for HD.

More than one million barriers fragment Europe's rivers.

Rivers support some of Earth's richest biodiversity1 and provide essential ecosystem services to society2, but they are often fragmented by barriers to free flow3. In Europe, attempts to quantify river connectivity have been hampered by the absence of a harmonized barrier database. Here we show that there are at least 1.2 million instream barriers in 36 European countries (with a mean density of 0.74 barriers per kilometre), 68 per cent of which are structures less than two metres in height that are often overlooked. Standardized walkover surveys along 2,715 kilometres of stream length for 147 rivers indicate that existing records underestimate barrier numbers by about 61 per cent. The highest barrier densities occur in the heavily modified rivers of central Europe and the lowest barrier densities occur in the most remote, sparsely populated alpine areas. Across Europe, the main predictors of barrier density are agricultural pressure, density of river-road crossings, extent of surface water and elevation. Relatively unfragmented rivers are still found in the Balkans, the Baltic states and parts of Scandinavia and southern Europe, but these require urgent protection from proposed dam developments. Our findings could inform the implementation of the EU Biodiversity Strategy, which aims to reconnect 25,000 kilometres of Europe's rivers by 2030, but achieving this will require a paradigm shift in river restoration that recognizes the widespread impacts caused by small barriers.

A mechanical approach to understanding the impact of the nematode Anguillicoloides crassus on the European eel swimbladder.

One of the most detrimental factors in the drastic decline of the critically endangered European eel (Anguilla anguilla) was the inadvertent introduction of the invasive nematode Anguillicoloides crassus Infection primarily affects the swimbladder, a gas-filled organ that enables the eel to control its depth in the water. A reduction in swimbladder function may be fatal for eel undergoing their spawning migration to the Sargasso Sea, a journey of over 5000 km. Although the physiological damage caused by this invasive parasite is well studied through the use of quantifiable gross pathological indices, providing a good measure of the swimbladder health status, they cannot separate the role of mechanical and morphological damage. Our study examined the appropriateness of three commonly used indices as a measure of mechanical damage by performing uniaxial tensile tests on swimbladder specimens obtained from an infected eel population. When the test results were compared with the gross pathological indices it was found that thickness correlated most strongly with mechanical damage, both confirming and, more importantly, explaining the counterintuitive findings of earlier work. In a damaged swimbladder, the immune response leads to a trade-off; increasing wall thickness raises the pressure required for organ rupture but decreases strength. The results indicate that for moderate infection the mechanical integrity of the swimbladder can be maintained. For severe infection, however, a reduction in mechanical integrity may reach a tipping point, thereby affecting the successful completion of their oceanic migration.

COVID-19 provides an opportunity to advance a sustainable UK fisheries policy in a post-Brexit brave new world.

Brexit creates a systemic shock that provides a unique opportunity for the UK to implement a new sustainable Fisheries Policy to better manage the multiple stocks on which future fishers will depend on leaving the European Union. At the same time, the global slowdown of commercial fishing as a result of COVID-19 has reduced pressure on some threatened stocks to levels not seen since the Second World War. In combination, Brexit and the COVID-19 slowdown have created a unique opportunity to facilitate the recovery of a threatened resource. Nevertheless, challenges remain as fisheries represent only 0.12% of UK economic output, presenting a risk that opportunities for more sustainable management will be lost during wider trade negotiations. Reduced fishing pressure during the COVID-19 era will enable stocks an opportunity to recover if supported by a new UK Fisheries Policy that focuses on: (a) re-establishing the role of Maximum Sustainable Yield to set limits that enable the recovery of fish populations initiated during the COVID-19 era; (b) ensuring that catch targets are set with the aim to maintain biomass at 120% of that which will achieve Maximum Sustainable Yield; (c) improving coherent resource management that also considers the expensive use of carbon associated with unsustainable fishing, and the need to protect fish throughout their life-cycle; and (d) constructing and effectively enforcing protection of a resilient network of Marine Protected Areas despite potential protests from EU member states.

Metabolic profiling shows pre-existing mitochondrial dysfunction contributes to muscle loss in a model of ICU-acquired weakness.

BACKGROUND: Surgery can lead to significant muscle loss, which increases recovery time and associates with increased mortality. Muscle loss is not uniform, with some patients losing significant muscle mass and others losing relatively little, and is likely to be accompanied by marked changes in circulating metabolites and proteins. Determining these changes may help understand the variability and identify novel therapeutic approaches or markers of muscle wasting. METHODS: To determine the association between muscle loss and circulating metabolites, we studied 20 male patients (median age, 70.5, interquartile range, 62.5-75) undergoing aortic surgery. Muscle mass was determined before and 7 days after surgery and blood samples were taken before surgery, and 1, 3, and 7 days after surgery. The circulating metabolome and proteome were determined using commercial services (Metabolon and SomaLogic). RESULTS: Ten patients lost more than 10% of the cross-sectional area of the rectus femoris (RFCSA ) and were defined as wasting. Metabolomic analysis showed that 557 circulating metabolites were altered following surgery (q < 0.05) in the whole cohort and 104 differed between wasting and non-wasting patients (q < 0.05). Weighted genome co-expression network analysis, identified clusters of metabolites, both before and after surgery, that associated with muscle mass and function (r = -0.72, p = 6 × 10-4 with RFCSA on Day 0, P = 3 × 10-4 with RFCSA on Day 7 and r = -0.73, P = 5 × 10-4 with hand-grip strength on Day 7). These clusters were mainly composed of acyl carnitines and dicarboxylates indicating that pre-existing mitochondrial dysfunction contributes to muscle loss following surgery. Surgery elevated cortisol to the same extent in wasting and non-wasting patients, but the cortisol:cortisone ratio was higher in the wasting patients (Day 3 P = 0.043 and Day 7 P = 0.016). Wasting patients also showed a greater increase in circulating nucleotides 3 days after surgery. Comparison of the metabolome with inflammatory markers identified by SOMAscan® showed that pre-surgical mitochondrial dysfunction was associated with growth differentiation factor 15 (GDF-15) (r = 0.79, P = 2 × 10-4 ) and that GDF-15, interleukin (IL)-8), C-C motif chemokine 23 (CCL-23), and IL-15 receptor subunit alpha (IL-15RA) contributed to metabolic changes in response to surgery. CONCLUSIONS: We show that pre-existing mitochondrial dysfunction and reduced cortisol inactivation contribute to muscle loss following surgery. The data also implicate GDF-15 and IL-15RA in mitochondrial dysfunction.