Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy.

Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest protein family genetically linked to CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused by YARS1 mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that human DI-CMTC-causing TyrRSE196K mis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for several mutant glycyl-tRNA synthetases linked to CMT type 2D (CMT2D). We then performed temporal neuromuscular assessments of YarsE196K mice modelling DI-CMT. We determined that YarsE196K homozygotes display a selective, age-dependent impairment in in vivo axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This impairment is replicated by injection of recombinant TyrRSE196K, but not TyrRSWT, into muscles of wild-type mice. Augmenting BDNF in DI-CMTC muscles, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a non-cell autonomous pathomechanism common to ARS-related neuropathies, and highlights the potential of boosting BDNF levels in muscles as a therapeutic strategy.

Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy.

Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest protein family genetically linked to CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused by YARS1 mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that human DI-CMTC-causing TyrRSE196K mis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for several mutant glycyl-tRNA synthetases linked to CMT type 2D (CMT2D). We then performed temporal neuromuscular assessments of YarsE196K mice modelling DI-CMT. We determined that YarsE196K homozygotes display a selective, age-dependent impairment in in vivo axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This impairment is replicated by injection of recombinant TyrRSE196K, but not TyrRSWT, into muscles of wild-type mice. Augmenting BDNF in DI-CMTC muscles, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a non-cell autonomous pathomechanism common to ARS-related neuropathies, and highlights the potential of boosting BDNF levels in muscles as a therapeutic strategy.

Ethical Concerns about Fashionable Dog Breeding.

The historical relationship between humans and dogs has involved selective breeding for various purposes, such as hunting, guarding, and service roles. However, over time, there has been a shift in preferences from functionality to aesthetics, which has influenced the diverse sizes, shapes, and coats of dog breeds. This review looks at fashionable dog breeding and questions the ethics of prioritising looks over health and behaviour. It aims to alert potential owners, breeders, and regulators to the importance of considering a dog's overall well-being, not just its appearance, which has resulted in fad breeding, leading to genetic disorders, health issues, and a loss of biodiversity. Ethical concerns arise from breeding brachycephalic breeds with respiratory conditions, inbreeding causing inherited disorders, and overbreeding popular breeds while shelter dogs remain unadopted. Additionally, the impact of cosmetic surgeries on popular dog breeds, as well as the neglect of behavioural traits in favour of physical characteristics and strict breeding practices are also considered. The current breeding model can have a negative impact on the emotional and cognitive well-being of dogs, resulting in issues such as aggression, anxiety, and other behavioural problems that can significantly reduce their overall quality of life. Unregulated breeding practices and the demand for rare breeds can lead to illegal breeding, compromising animal welfare. Prospective owners, veterinarians, kennel clubs, and legislators all need to play a responsible role in protecting animals.

Enhanced antimicrobial efficacy of biogenic ZnO nanoparticles through UV-B activation: A novel approach for textile garment.

Zinc oxide nanoparticles (ZnO NP) are characterized by novel properties which have been attracting the attention of different lines of research due to their wide applicability. Obtaining this nanomaterial is strongly linked to biogenic synthesis methods, which have also been developed in this research, using Coriandrum sativum extract as a reducing agent. ZnO NPs have been properly characterized by techniques to evaluate their morphology by transmission electron microscopy (TEM) and elemental analysis by EDX. The evaluation of the antimicrobial and antifungal effects is linked to the use of a system provided by "locker sanitizer" equipment, which has been designed and built as part of this research, and is intended to treat textile garments by nebulizing the ZnO NP colloid (99.08 µg/mL) + UV-B, water + UV-B, and UV-B only, and also to evaluate the influence of the treatment time for 1, 2 and 3 min. In this sense, it is known that the nanomaterial used shows a better response to UV light because more hydroxyl radicals are produced, leading to a higher reaction rate, which results in greater efficiency in inhibitory processes. The results show that the use of the locker sanitizer is more efficient when using ZnO NP + UV-B light since it achieved 100 % growth inhibition against E. coli, C. albicans, and A. brasiliensis, and >99 % against S. aureus, after 3 min of treatment.

Dendritic voltage imaging maps the biophysical basis of plateau potentials in the hippocampus.

Dendrites on neurons integrate synaptic inputs to determine spike timing. Dendrites also convey back-propagating action potentials (bAPs) which interact with synaptic inputs to produce plateau potentials and to mediate synaptic plasticity. The biophysical rules which govern the timing, spatial structures, and ionic character of dendritic excitations are not well understood. We developed molecular, optical, and computational tools to map sub-millisecond voltage dynamics throughout the dendritic trees of CA1 pyramidal neurons under diverse optogenetic and synaptic stimulus patterns, in acute brain slices. We observed history-dependent bAP propagation in distal dendrites, driven by locally generated Na + spikes (dSpikes). Dendritic depolarization creates a transient window for dSpike propagation, opened by A-type K V channel inactivation, and closed by slow Na V inactivation. Collisions of dSpikes with synaptic inputs triggered calcium channel and N-methyl-D-aspartate receptor (NMDAR)-dependent plateau potentials, with accompanying complex spikes at the soma. This hierarchical ion channel network acts as a spike-rate accelerometer, providing an intuitive picture of how dendritic excitations shape associative plasticity rules.

Social anxiety disorder-associated gut microbiota increases social fear.

Social anxiety disorder (SAD) is a crippling psychiatric disorder characterized by intense fear or anxiety in social situations and their avoidance. However, the underlying biology of SAD is unclear and better treatments are needed. Recently, the gut microbiota has emerged as a key regulator of both brain and behaviour, especially those related to social function. Moreover, increasing data supports a role for immune function and oxytocin signalling in social responses. To investigate whether the gut microbiota plays a causal role in modulating behaviours relevant to SAD, we transplanted the microbiota from SAD patients, which was identified by 16S rRNA sequencing to be of a differential composition compared to healthy controls, to mice. Although the mice that received the SAD microbiota had normal behaviours across a battery of tests designed to assess depression and general anxiety-like behaviours, they had a specific heightened sensitivity to social fear, a model of SAD. This distinct heightened social fear response was coupled with changes in central and peripheral immune function and oxytocin expression in the bed nucleus of the stria terminalis. This work demonstrates an interkingdom basis for social fear responses and posits the microbiome as a potential therapeutic target for SAD.

Postharvest Storage Differentially Modulates the Enzymatic and Non-Enzymatic Antioxidant System of the Exocarp and Mesocarp of Hass Avocado: Implications for Disorders.

The present study evaluated the performance of some enzymatic and non-enzymatic antioxidant systems against oxidative stress for 10 to 30 d of refrigeration (R) and 15 to 50 d in controlled atmosphere (CA) conditions in both exocarp and mesocarp of Hass avocados from early and late harvests and at shelf life (SL) or consumption maturity. The possible relationship of the antioxidant systems with the occurrence of physiological disorders is also evaluated. The results indicate that the enzymatic system-superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), phenylalanine ammonium lyase (PAL) and polyphenoloxidase (PPO)-as well as the non-enzymatic system-such as phenolic compounds (PC)-showed different responses to the stress generated during storage and shelf life. In general, SOD, CAT, PAL and PPO did not significantly vary in storage (R or CA). At consumption maturity, SOD, POD and PAL activities decreased in the mesocarp (RSL and CASL), while CAT increased in the exocarp for CASL15-50d. PC instead decreased in the exocarp as the harvest period progressed while it increased in the mesocarp. Physiological disorders (dark spots) showed only in refrigeration on the exocarp at R30d and in mesocarp at RSL30d coincident with low SOD and low SOD and POD activity values, as well as low PC contents (p-coumaric and its derivatives and caffeic acid derivatives), respectively. The results support the use of CA as a postharvest technology to prevent the development of physiological disorders through the joint action of antioxidative defenses during avocado transport to distant markets until consumption maturity is reached.

Cu2O, ZnO, and Ag/ Cu2O nanoparticles synthesized by biogenic and chemical route and their effect on Pseudomonas aeruginosa and Candida albicans.

Pseudomonas aeruginosa and Candida albicans are two important pathogens in public health due to the infections they cause in immunocompromised patients and with hospital stay, increasing morbimortality rates. Three groups of Cu2O, ZnO, and Ag/Cu2O nanoparticles were synthesized and characterized physicochemically and confronted to P. aeruginosa and C. albicans to determine their antibacterial effect. Statistical analyses were performed using Analysis of Variance (ANOVA) (p < 0.001). The structures of Cu2O, ZnO, and Ag/Cu2O nanoparticles were spherical, sized 6 nm, 10 nm, and 50 nm for Ag, Cu2, and Zn metals, respectively. Furthermore, a 100% antibacterial and antifungal effect against Pseudomonas aeruginosa and Candida albicans was observed for Cu2O, ZnO, and Ag/Cu2O nanoparticles respectively. It is concluded from these findings that the nanoparticles synthesized by biogenic and chemical route had a good size between 6 and 50 nm and that Cu2O, ZnO, and Ag/Cu2O nanoparticles presented an excellent antibacterial (100% growth inhibition) effect against P. aeruginosa and C. albicans (p < 0.001) compared to the control.

Evaluation of the antiviral activity of ultraviolet light and zinc oxide nanoparticles on textile products exposed to Avian coronavirus.

This research has developed a piece of sanitizing locker-model equipment for textiles exposed to avian coronavirus, which has been put under the influence of UV light, UV + zinc oxide nanoparticles (phytosynthesized ZnONP), and water + UV, and, in turn, under the influence of the exposure time (60, 120, 180 s). The results linked to the phytosynthesis of ZnONP indicate a novel method of fabricating nanostructured material, nanoparticles with spherical morphology and an average size of 30 nm. The assays were made based on the viral viability of avian coronavirus according to the mortality of SPF embryonated eggs and a Real-Time PCR for viral load estimation. This was a model to evaluate the sanitizing effects against coronaviruses since they share a very similar structure and chemistry with SAR-CoV-2. The influence of the type of textile treatment evidenced the potential effect of the sanitizing UV light, which achieved 100% of embryo viability. The response of the ZnONP + UV nebulization showed a notorious influence of photoactivation according to the exposure time, and the 60-s treatment achieved a decrease of 88.9% in viral viability, compared to 77.8% and 55.6% corresponding to the 120 and 180-s treatments, respectively. Regarding the decrease in viral load between the types of treatments, UV 180 s reduced 98.42% and UV 60 s + ZnONP reduced 99.46%, respectively. The results show the combinatorial effect of UV light and zinc nanoparticles in decreasing the viral viability of avian coronavirus, as a model of other important coronaviruses in public health such as SARS-CoV-2.

Biogenic production of silver, zinc oxide, and cuprous oxide nanoparticles, and their impregnation into textiles with antiviral activity against SARS-CoV-2.

Nanotechnology is being used to fight off infections caused by viruses, and one of the most outstanding nanotechnological uses is the design of protective barriers made of textiles functionalized with antimicrobial agents, with the challenge of combating the SARS-CoV-2 virus, the causal agent of COVID-19. This research is framed within two fundamental aspects: the first one is linked to the proposal of new methods of biogenic synthesis of silver, cuprous oxide, and zinc oxide nanoparticles using organic extracts as reducing agents. The second one is the application of nanomaterials in the impregnation (functionalization) of textiles based on methods called "in situ" (within the synthesis), and "post-synthesis" (after the synthesis), with subsequent evaluation of their effectiveness in reducing the viral load of SARS-CoV-2. The results show that stable, monodisperse nanoparticles with defined geometry can be obtained. Likewise, the "in situ" impregnation method emerges as the best way to adhere nanoparticles. The results of viral load reduction show that 'in situ' textiles with Cu2O NP achieved a 99.79% load reduction of the SARS-CoV-2 virus.

Phosphorus recovery from aqueous solutions using Bioclastic Granules (Lithothamnium calcareum).

Against the growing world demand for food and the possibility of recovering some nutrients, this work focused on the evaluation of the use of Bioclastic Granules (BG) from the algae Lithothamnium calcareum as sorbent material for the removal/recovery of phosphorus from aqueous solutions. The main variables that affect the sorption process, pH, initial concentration of phosphate, and GB, as well as the contact time, were evaluated. The effect of pH was very significant, obtaining the best results of PO43- removal at pH 5. In the coarser granulometric fractions (+ 106 - 150 and + 210 - 300 µm), the best removals were observed (around 75%). Regarding the initial PO43- concentration in the solutions, the highest removal (in the range of 74 to 78%) was observed in the lowest concentrations (5 to 70 mg L-1) and the best uptake (10 to 14 mg g-1) at higher concentrations (200 to 420 mg L-1). The PO43- sorption data fitted the Freundlich model well, with kF of 1.35 L mg-1 and n of 2.43. A qmax of 14.35 mg g-1 was obtained using the Langmuir model. Regarding the sorption data over time, a better fit to the pseudo-first-order kinetic model was observed, obtaining a calculated qeq of 6.56 mg g-1 and a k1 of 0.0073 min-1. The incorporation of PO43- ions in the GB structure was confirmed through the characterization results before and after the sorption experiments using X-ray fluorescence (FRX) and scanning electron microscopy (SEM) techniques.

Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice.

Gain-of-function mutations in the housekeeping gene GARS1, which lead to the expression of toxic versions of glycyl-tRNA synthetase (GlyRS), cause the selective motor and sensory pathology characterizing Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor tropomyosin receptor kinase receptor B (TrkB), underlie CMT type 2D (CMT2D); however, our pathomechanistic understanding of this untreatable peripheral neuropathy remains incomplete. Through intravital imaging of the sciatic nerve, we show that CMT2D mice displayed early and persistent disturbances in axonal transport of neurotrophin-containing signaling endosomes in vivo. We discovered that brain-derived neurotrophic factor (BDNF)/TrkB impairments correlated with transport disruption and overall CMT2D neuropathology and that inhibition of this pathway at the nerve-muscle interface perturbed endosome transport in wild-type axons. Accordingly, supplementation of muscles with BDNF, but not other neurotrophins, completely restored physiological axonal transport in neuropathic mice. Together, these findings suggest that selectively targeting muscles with BDNF-boosting therapies could represent a viable therapeutic strategy for CMT2D.

Cu2O nanoparticles synthesized by green and chemical routes, and evaluation of their antibacterial and antifungal effect on functionalized textiles.

The potential for the application of metal-containing nanomaterials at the nanoscale promotes the opportunity to search for new methods for their elaboration, with special attention to those sustainable methods. In response to these challenges, we have investigated a new method for green synthesis of cuprous oxide nanoparticles (Cu2O NPs) using Myrciaria dubia juice as an organic reductant and, comparing it with chemical synthesis, evaluating in both cases the influence of the volume of the organic (juice) and chemical (ascorbic acid) reductants, for which a large number of techniques such as spectrophotometry, EDX spectrometry, TEM, SEM, DLS, FTIR spectroscopy have been used. Likewise, the nanomaterial with better morphological characteristics, stability, and size homogeneity has been applied in the functionalization of textiles by means of in situ and post-synthesis impregnation methods. The success of the synthesis process has been demonstrated by the antimicrobial activity (bacteria and fungi) of textiles impregnated with Cu2O NPs.

A multiomics integrative analysis of color de-synchronization with softening of 'Hass' avocado fruit: A first insight into a complex physiological disorder.

Exocarp color de-synchronization with softening of 'Hass' avocado is a relevant recurrent problem for the avocado supply chain. This study aimed to unravel the mechanisms driving this de-synchronization integrating omics datasets from avocado exocarp of different storage conditions and color phenotypes. In addition, we propose potential biomarkers to predict color synchronized/de-synchronized fruit. Integration of transcriptomics, proteomics and metabolomics and network analysis revealed eight transcription factors associated with differentially regulated genes between regular air (RA) and controlled atmosphere (CA) and twelve transcription factors related to avocado fruit color de-synchronization control in ready-to-eat stage. CA was positively correlated to auxins, ethylene, cytokinins and brassinosteroids-related genes, while RA was characterized by enrichment of cell wall remodeling and abscisic acid content associated genes. At ready-to-eat higher contents of flavonoids, abscisic acid and brassinosteroids were associated with color-softening synchronized avocados. In contrast, de-synchronized fruit revealed increases of jasmonic acid, salicylic acid and auxin levels.

The gut microbiota alone and in combination with a social stimulus regulates cocaine reward in the mouse.

The gut microbiota is a key factor in the maintenance of physiological homeostasis and immunity. Correlational studies have demonstrated that alterations in microbiota composition have been associated with addiction. Moreover, animal studies have confirmed a link between reward and social processes, which may be shaped by the gut microbiota thus influencing neurodevelopment and the programming of social behaviors across diverse animal species. However, whether there is an interaction between the microbiota and social reward processes in the context of drug reward remains unclear. To this end, we explored the influence of gut microbiota in regulating behaviourally conditioned responses to different rewards (cocaine and social interactions). Depletion of the intestinal microbiota resulted in differential reward responses to both drug and social stimuli with an attenuation of the former and enhancement of the latter independent of concomitant immune changes. Moreover, the combination of depleting the gut microbiota in the presence of a positive social stimulus attenuates cocaine reward. Together these data suggest that the two-pronged approach of targeting the microbiota and enhancing social behaviour could constitute a valuable component in reducing harm in drug use by altering the salient effects of cocaine.

In vitro and in vivo biotransformation of glucosinolates from mashua (Tropaeolum tuberosum) by lactic acid bacteria.

Mashua (Tropaeolum tuberosum) is an Andean tuber with a high content of glucosinolates (GLSs). GLSs subjected to biotransformation by plant enzymes or enzymes of the gastrointestinal microbiota give rise to biologically active compounds, to which chemo preventive properties are attributed. In this work, the biotransformation of mashua GLSs was evaluated in vitro by six strains of lactic acid bacteria (LAB) and in vivo using rats with and without previous LAB dosing. The results showed that L. rhamnosus GG utilized the totality of glucosinalbin and glucotropaeolin, and 46.7 % of glucoaubrietin. Four GLSs derivatives were detected. The GLSs were absorbed and metabolized by the rats with low contents in feces (0.02 %) and urine (0.59 %) and were detected up to 3 h after consumption in plasma. The results showed that probiotic bacteria play an important role in transforming GLSs into beneficial compounds for the health of consumers.

A Systematic Review of Medical Cannabinoids Dosing in Human.

PURPOSE: This systematic review assesses currently available clinical information on which cannabinoids and what range of doses have been used to achieve positive effects in a diversity of medical context. METHODS: The data were collected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol guidelines. Inclusion criteria were articles that assessed administration of any cannabinoid to any clinical population, reported in the ClinicalTrials.gov or PubMed databases, that involved a comparison with other treatment or placebo and a result measurement to assess the effectiveness or ineffectiveness of the cannabinoid. Exclusion criteria were review or letter; articles not in the English language; not full-text articles; not a clinical trial, case report, case series, open-label trial, or pilot study; administration in animals, in vitro, or in healthy participants; cannabinoids administered in combination with other cannabinoids (except for cannabidiol [CBD] or tetrahydrocannabinol [THC]) or as whole cannabis extracts; no stated concentration; inhalation or smoke as a route of administration; and no results described. The articles were assessed by the risk of bias. FINDING: In total, 1668 articles were recovered, of which 55 studies met the inclusion criteria for 21 diseases. Positive effects were reported in clinical studies: 52% with THC (range, 0.01-0.5 mg/kg/d [0.62-31 mg/d]), 74% with CBD (range, 1-50 mg/kg/d [62-3100 mg/d]), 64% with THC-CBD (mean, 1:1.3 mg/kg/d [ratio, 1:1]), and 100% with tetrahydrocannabivarin (THCV) (0.2 mg/kg/d). IMPLICATIONS: THC, CBD, and THCV can regulate activity in several pathologies. New studies of cannabinoids are highly encouraged because each patient is unique and requires a unique cannabinoid medication.

The live biotherapeutic Blautia stercoris MRx0006 attenuates social deficits, repetitive behaviour, and anxiety-like behaviour in a mouse model relevant to autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by deficits in social behaviour, increased repetitive behaviour, anxiety and gastrointestinal symptoms. The aetiology of ASD is complex and involves an interplay of genetic and environmental factors. Emerging pre-clinical and clinical studies have documented a potential role for the gut microbiome in ASD, and consequently, the microbiota represents a potential target in the development of novel therapeutics for this neurodevelopmental disorder. In this study, we investigate the efficacy of the live biotherapeutic strain, Blautia stercoris MRx0006, in attenuating some of the behavioural deficits in the autism-relevant, genetic mouse model, BTBR T+ Itpr3tf/J (BTBR). We demonstrate that daily oral administration with MRx0006 attenuates social deficits while also decreasing repetitive and anxiety-like behaviour. MRx0006 administration increases the gene expression of oxytocin and its receptor in hypothalamic cells in vitro and increases the expression of hypothalamic arginine vasopressin and oxytocin mRNA in BTBR mice. Additionally at the microbiome level, we observed that MRx0006 administration decreases the abundance of Alistipes putredinis, and modulates the faecal microbial metabolite profile. This alteration in the metabolite profile possibly underlies the observed increase in expression of oxytocin, arginine vasopressin and its receptors, and the consequent improvements in behavioural outcomes. Taken together, these findings suggest that the live biotherapeutic MRx0006 may represent a viable and efficacious treatment option for the management of physiological and behavioural deficits associated with ASD.