Gene editing and Rett syndrome: does it make the cut?

Rett syndrome (RTT) is a rare neurogenetic disorder caused by pathogenic variants of the Methyl CpG binding protein 2 (MECP2) gene. The RTT is characterized by apparent normal early development followed by regression of communicative and fine motor skills. Comorbidities include epilepsy, severe cognitive impairment, and autonomic and motor dysfunction. Despite almost 60 clinical trials and the promise of a gene therapy, no cure has yet emerged with treatment remaining symptomatic. Advances in understanding RTT has provided insight into the complexity and exquisite control of MECP2 expression, where loss of expression leads to RTT and overexpression leads to MECP2 duplication syndrome. Therapy development requires regulated expression that matches the spatiotemporal endogenous expression of MECP2 in the brain. Gene editing has revolutionized gene therapy and promises an exciting strategy for many incurable monogenic disorders, including RTT, by editing the native locus and retaining endogenous gene expression. Here, we review the literature on the currently available editing technologies and discuss their limitations and applicability to the treatment of RTT

Geosmin suppresses defensive behaviour and elicits unusual neural responses in honey bees

Geosmin is an odorant produced by bacteria in moist soil. It has been found to be extraordinarily relevant to some insects, but the reasons for this are not yet fully understood. Here we report the first tests of the effect of geosmin on honey bees. A stinging assay showed that the defensive behaviour elicited by the bee's alarm pheromone component isoamyl acetate (IAA) is strongly suppressed by geosmin. Surprisingly, the suppression is, however, only present at very low geosmin concentrations, and disappears at higher concentrations. We investigated the underlying mechanisms at the level of the olfactory receptor neurons by means of electroantennography, finding the responses to mixtures of geosmin and IAA to be lower than to pure IAA, suggesting an interaction of both compounds at the olfactory receptor level. Calcium imaging of the antennal lobe (AL) revealed that neuronal responses to geosmin decreased with increasing concentration, correlating well with the observed behaviour. Computational modelling of odour transduction and coding in the AL suggests that a broader activation of olfactory receptor types by geosmin in combination with lateral inhibition could lead to the observed non-monotonic increasing-decreasing responses to geosmin and thus underlie the specificity of the behavioural response to low geosmin concentrations

Banks of Cryopreserved Skin from Live Donors and Total Skin Allografts in the Surgery of Major Burnt Patients

Scarectomy and prompt coverage are some of the main cornerstones of the actual treatment of major burnt patients. This coverage can be definitive using autologous tissues or temporary with allografts, xenografts, and/or biosynthetic products. Skin allografts (SAs) are the gold standard therapeutic alternative among temporary coverages, since they mimic skin functions. However, cadaveric skin donation and procurement, a common SA source, are infrequent. On the other hand, there is a significant number of patients that, given their health condition, large amounts of skin must be resected for their clinical recovery, including patients submitted to corporal contouring surgeries with esthetic and/or reconstructive motives, usually eliminating the redundant skin as biological waste. This study describes a skin bank model from live donors and cryopreserved total skin cutaneous allografts (CTSCAs), a new type of SA resulting from a particular skin processing

Effects of plant diversity on productivity strengthen over time due to trait-dependent shifts in species overyielding

Plant diversity effects on community productivity often increase over time. Whether the strengthening of diversity effects is caused by temporal shifts in species-level overyielding (i.e., higher species-level productivity in diverse communities compared with monocultures) remains unclear. Here, using data from 65 grassland and forest biodiversity experiments, we show that the temporal strength of diversity effects at the community scale is underpinned by temporal changes in the species that yield. These temporal trends of species-level overyielding are shaped by plant ecological strategies, which can be quantitatively delimited by functional traits. In grasslands, the temporal strengthening of biodiversity effects on community productivity was associated with increasing biomass overyielding of resource-conservative species increasing over time, and with overyielding of species characterized by fast resource acquisition either decreasing or increasing. In forests, temporal trends in species overyielding differ when considering above- versus belowground resource acquisition strategies. Overyielding in stem growth decreased for species with high light capture capacity but increased for those with high soil resource acquisition capacity. Our results imply that a diversity of species with different, and potentially complementary, ecological strategies is beneficial for maintaining community productivity over time in both grassland and forest ecosystems.O

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Effects of plant diversity on productivity strengthen over time due to trait-dependent shifts in species overyielding

Plant diversity effects on community productivity often increase over time. Whether the strengthening of diversity effects is caused by temporal shifts in species-level overyielding (i.e., higher species-level productivity in diverse communities compared with monocultures) remains unclear. Here, using data from 65 grassland and forest biodiversity experiments, we show that the temporal strength of diversity effects at the community scale is underpinned by temporal changes in the species that yield. These temporal trends of species-level overyielding are shaped by plant ecological strategies, which can be quantitatively delimited by functional traits. In grasslands, the temporal strengthening of biodiversity effects on community productivity was associated with increasing biomass overyielding of resource-conservative species increasing over time, and with overyielding of species characterized by fast resource acquisition either decreasing or increasing. In forests, temporal trends in species overyielding differ when considering above- versus belowground resource acquisition strategies. Overyielding in stem growth decreased for species with high light capture capacity but increased for those with high soil resource acquisition capacity. Our results imply that a diversity of species with different, and potentially complementary, ecological strategies is beneficial for maintaining community productivity over time in both grassland and forest ecosystems

3D characterization of magnetic phases through neutron polarization contrast tomography

The advancement of laser-based metal additive manufacturing has enabled the production of near net shape complex geometries. Understanding the microstructural features of materials is crucial for accurate modeling of their mechanical behavior, particularly with regard to strain- or thermal-induced martensitic phase transformations in ferrous alloys and steels. For example, the formation of BCC α′-martensite can strengthen materials while preserving ductility of the dominating austenitic phase. However, in components where the shape memory effect is attributed to the reversible formation of ε-martensite, the accumulation of deformation-induced α′-martensite is an undesired, irreversible degradation mechanism. This study presents a novel tomographic approach utilizing polarization contrast neutron imaging for the 3D volumetric characterization of magnetic crystallographic phases, especially those present in low phase fractions that are typically undetectable with traditional techniques. The technique is applied to the study of strain-induced martensitic phase transformations in additively manufactured lattice structures made of high-Mn steels, which form small fractions of α′-martensite upon deformation. The results demonstrate the value of this technique for characterizing entire components and complex geometries found in numerous technological applications

Trail pheromone identification in the ant Crematogaster scutellaris

Abstract In this work, we identified the trail pheromone of the ant Crematogaster scutellaris. We combined gas chromatography–mass spectrometry analysis of extracts from the hind tibia, the location of the respective glands, with automated trail following assays. The study found tridecan-2-ol to be the strongest discriminator between hind tibia and other body part extracts. Tridecan-2-ol elicited trail-following behaviour at concentrations of 1 ng/µL. A separation of the enantiomers showed responses to (R)-tridecan-2-ol already at 0.001 ng/µL and only at a 1000-fold higher concentration for (S)-tridecan-2-ol, suggesting that only the R enantiomer is used by C. scutellaris in its natural environment. We also found strong behavioural responses to 2-dodecanol, a substance that was not detectable in the hind tibia extract of C. scutellaris, but which has been reported to be the trail pheromone of the related species C. castanea. We discuss the contribution of these results to the 'dissection and reconstruction' of strategies and mechanisms underlying the social organization of ants

Research data for paper "Geosmin suppresses defensive behaviour and elicits unusual neural responses in honey bees"

Research data for paper published in Scientific Reports journal March 2023  This data explores the effects of Geosmin on honeybees and has three separate parts:  1. Behavioural data on the stinging response of bees towards a dummy in the presence of the alarm pheromone and Geosmin 2. Electro-antennogram (EAG) data of the response to Geosmin on bees' antenna 3. Calcium imaging data illustrating the neural response to Geosmin in the honey bee antennal lobe. Data & File Overview File List:  Bee_Aggression_Behaviour.csv: Bees' stinging responses towards a rotating dummy  Bee_AL_Calcium_imaging.csv: Calcium imaging time traces for individual odour stimuli and glomeruli in all bees  Bee_EAG_Data.csv: Electroantennography response amplitudes for individual odour stimuli in all bees Methodological Information all Methods described in: Scarano F, Deivarajan Suresh M, Tiraboschi E, Cabirol A, Nouvian M, Nowotny T, Haase A.  Geosmin suppresses defensive behaviour and elicits unusual neural responses in honey bees. Sci Rep 13:3851 (2023)   Data-specific Information for: 'Bee_Aggression_Behaviour.csv' The data file contains observational data from an aggression assay, where 325 bee dyads were inserted into an arena with a rotating dummy. Data indicates whether a behaviour was observed or not from one or both bees. Further details in the Methods sections of Scarano et al. 2021 Number of variables/columns: 17 Number of cases/rows: 324 Variable List:  A) Day: Date in which bees were tested, DD/MM/YYYY B) Weather: Describes the weather on the trial date, Sunny / Cloudy C) Hive: Hive colour recognised by the paint colour from which the bees have been acquired, Orange / White / Green / Yellow D) Dummy: Which of two arenas used in that behavioural trial, A / B E) Group: Represents the odours - VOCs and its mixtures with the respective concentrations, IAA / Geosmin6 / Geosmin3 / IAAGeo3 / IAAGeo6 / Control, Concentrations: 3 (10^-3) & 6 (10^-6) F) Sting.Bee1: Represents if bee one exhibits stinging behaviour, 0 (no) / 1 (yes), binary  G) Sting.Bee2: Represents if bee two exhibits stinging behaviour, 0 (no) / 1 (yes), binary  H) Recruit.Bee1: Represents if bee one exhibits recruiting behaviour, 0 (no) / 1 (yes), binary  I) Recruit.Bee2: Represents if bee two exhibits recruiting behaviour, 0 (no) / 1 (yes), binary  J) Grooming/Calm: Represents if the bees exhibit grooming or calm behaviour, 0 (none) /1 /2, number of bees K) Batch: Represents in which time batch the trials were conducted, 1 (Morning) / 2 (Afternoon), numerical – time period L) number.sting: Represents number of bees stinging in a trial, 0/1/2, number of bees M) number.recruit: Represents number of bees recruiting in a trial, 0/1/2, number of bees N) sting.first: Represents if the stinging behaviour was exhibited first in a trial, 0 (no) / 1 (yes), binary  O) recruit.first: Represents if the recruiting behaviour was exhibited first in a trial, 0 (no) / 1 (yes), binary P) b.sting: Represents if there was any stinging behaviour exhibited by the two bees during that trial, 0 (no) / 1 (yes), binary  Q) b.recruit: Represents if there was any recruiting behaviour exhibited by the two bees during that trial, 0 (no) / 1 (yes), binary Data-specific Information for: 'Bee_EAG_Data.csv' Data are electroantennography responses for 24 antennas exposed to different odour stimuli. Data points are voltage change amplitudes with respect to the baseline, averaged over the 1s stimulus duration. Further datails in the Methods sections of Scarano et al. 2021 Number of variables/columns: 16 Number of cases/rows: 24 Variable List: A) Bee: subject numbers B-P) Responses to different Odours and Concentrations Values are average potential change (over 10 repetitions) in response to the presented odour stimuli in units of Volt Odours presented:  Control = pure mineral oil (solvent)  Geo = geosmin in mineral oil at a concentration indicated in brackets  IAA = Isoamil acetate in mineral oil at a concentration indicated in brackets  B) Control mineral oil C) Geo (10^-6)  D) Geo (10^-5)  E) Geo (10^-4)  F) Geo (10^-3)  G) IAA (10^-3)  H) IAA (10^-3)+ Geo (10^-6)  I) IAA (10^-3)+ Geo (10^-5)  J) IAA (10^-3)+ Geo (10^-4)  K) IAA (10^-3)+ Geo (10^-3)  L) IAA (10^-1)  M) IAA (10^-1)+ Geo (10^-6)  N) IAA (10^-1)+ Geo (10^-5)  O) IAA (10^-1)+ Geo (10^-4)  P) IAA (10^-1)+ Geo (10^-3)  Data-specific Information for: 'Bee_AL_Calcium_imaging.csv' The data file contains response curve from up to 19 glomeruli in the antennal lobe of 14 bees, data are relative changes in fluorescence averaged over the glomerular area. The fluorescence changes stem from projection neurons that were stained by backfill injection with the calcium-sensitive dye fura-dextrane. Further details in Methods sections of Scarano et al. 2021 Number of variables/columns: 95 Number of cases/rows: 1720 Variable List: A) Bee-id: Subject number B) Glo_id: Glomerulus number following bee antennal lobe standard atlas nomenclature for tract T1 C) Odour: Stimulus odour type Geo6 = Geosmin at concentration 10^-6 in mineral oil Geo3 = Geosmin at concentration 10^-3 in mineral oil IAA = Isoamyl acetate at concentration 10^-1 in mineral oil 3Hex = 3-hexanol at concentration 5x10^-3 in mineral oil acetoph = Acetophenone at concentration 5x10^-3 in mineral oil non = 1-nonanol at concentration 5x10^-3 in mineral oil IAA-Glo are mixtures of both odours D) Response: Automatized response classification (1 activated, 2 background activity, 2 inhibited) E-CQ) Frame_1-91: Glomerular response curves, 91 frames, 10.033 frames/s,  Curves cover a 1s prestimulus interval (frames 1-30), 1s stimulus (frames 31-60), and 1s post stimulus (frames 61-91). Values are fluorescence changes in percent, averaged over the glomerular area, background subtracted and normalized with respect to the background. Article Abstract Geosmin is an odorant produced by bacteria in moist soil. It has been found to be extraordinarily relevant to some insects, but the reasons for this are not yet fully understood. Here we report the first tests of the effect of geosmin on honey bees. A stinging assay showed that the defensive behaviour elicited by the bee’s alarm pheromone component isoamyl acetate (IAA) is strongly suppressed by geosmin. Surprisingly, the suppression is, however, only present at very low geosmin concentrations, and disappears at higher concentrations. We investigated the underlying mechanisms at the level of the olfactory receptor neurons by means of electroantennography, finding the responses to mixtures of geosmin and IAA to be lower than to pure IAA, suggesting an interaction of both compounds at the olfactory receptor level. Calcium imaging of the antennal lobe (AL) revealed that neuronal responses to geosmin decreased with increasing concentration, correlating well with the observed behaviour. Computational modelling of odour transduction and coding in the AL suggests that a broader activation of olfactory receptor types by geosmin in combination with lateral inhibition could lead to the observed non-monotonic increasing–decreasing responses to geosmin and thus underlie the specificity of the behavioural response to low geosmin concentrations.  Links to other resources relating to the data Computational modelling software that aims at reproducing the Calicum and EAG data indcluded here, is available on https://github.com/tnowotny/bee_al_2021</p