Neddylation orchestrates the complex transcriptional and posttranscriptional program that drives Schwann cell myelination.

Myelination is essential for neuronal function and health. In peripheral nerves, >100 causative mutations have been identified that cause Charcot-Marie-Tooth disease, a disorder that can affect myelin sheaths. Among these, a number of mutations are related to essential targets of the posttranslational modification neddylation, although how these lead to myelin defects is unclear. Here, we demonstrate that inhibiting neddylation leads to a notable absence of peripheral myelin and axonal loss both in developing and regenerating mouse nerves. Our data indicate that neddylation exerts a global influence on the complex transcriptional and posttranscriptional program by simultaneously regulating the expression and function of multiple essential myelination signals, including the master transcription factor EGR2 and the negative regulators c-Jun and Sox2, and inducing global secondary changes in downstream pathways, including the mTOR and YAP/TAZ signaling pathways. This places neddylation as a critical regulator of myelination and delineates the potential pathogenic mechanisms involved in CMT mutations related to neddylation.

Neuropeptide Y receptor 1 and galanin receptor 2 (NPY1R-GALR2) interactions in the dentate gyrus and their relevance for neurogenesis and cognition.

Introduction: This study may unveil novel insights into the interactions between neuropeptide Y receptor 1 (NPY1R) and galanin receptor 2 (GALR2), in the dentate gyrus of the dorsal hippocampus, shedding light on their role in neurogenesis and cognitive functions. Existing literature highlights the potential of these interactions in enhancing learning and memory, yet detailed mechanisms remain underexplored. Methods: Utilizing intracerebroventricular injections of GALR2 and NPY1R agonists in Sprague-Dawley male rats, we examined neurogenesis via markers PCNA and DCX, and memory consolidation through the object-in-place task over a three-week period. Results: Significant increases in NPY1R-GALR2 co-localization and neuroblast proliferation were observed, alongside enhanced memory consolidation. These findings suggest a synergistic effect of NPY1R and GALR2 activation on cognitive functions. Discussion: Our findings may foster the development of novel heterobivalent or multitargeting drugs, affecting NPY1R-GALR2 interaction, and suggest a future pharmacogical strategy for improving learning and memory found in many brain diseases. Further research is encouraged to explore these mechanisms in pathological models.

An international review of the characteristics of viral nucleic acid-amplification testing (NAT) reveals a trend towards the use of smaller pool sizes and individual donation NAT.

BACKGROUND AND OBJECTIVES: Nucleic acid-amplification testing (NAT) is used for screening blood donations/donors for blood-borne viruses. We reviewed global viral NAT characteristics and NAT-yield confirmatory testing used by blood operators. MATERIALS AND METHODS: NAT characteristics and NAT-yield confirmatory testing used during 2019 was surveyed internationally by the International Society of Blood Transfusion Working Party Transfusion-Transmitted Infectious Diseases. Reported characteristics are presented herein. RESULTS: NAT was mainly performed under government mandate. Human immunodeficiency virus (HIV), hepatitis C virus (HCV) and hepatitis B virus (HBV) NAT was performed on all donors and donation types, while selective testing was reported for West Nile virus, hepatitis E virus (HEV), and Zika virus. Individual donation NAT was used for HIV, HCV and HBV by ~50% of responders, while HEV was screened in mini-pools by 83% of responders performing HEV NAT. Confirmatory testing for NAT-yield samples was generally performed by NAT on a sample from the same donation or by NAT and serology on samples from the same donation and a follow-up sample. CONCLUSION: In the last decade, there has been a trend towards use of smaller pool sizes or individual donation NAT. We captured characteristics of NAT internationally in 2019 and provide insights into confirmatory testing approaches used for NAT-yields, potentially benefitting blood operators seeking to implement NAT.

International review of blood donation nucleic acid amplification testing.

BACKGROUND AND OBJECTIVES: Nucleic acid amplification testing (NAT), in blood services context, is used for the detection of viral and parasite nucleic acids to reduce transfusion-transmitted infections. This project reviewed NAT for screening blood donations globally. MATERIALS AND METHODS: A survey on NAT usage, developed by the International Society of Blood Transfusion Working Party on Transfusion-transmitted Infectious Diseases (ISBT WP-TTID), was distributed through ISBT WP-TTID members. Data were analysed using descriptive statistics. RESULTS: Forty-three responses were received from 32 countries. Increased adoption of blood donation viral screening by NAT was observed over the past decade. NAT-positive donations were detected for all viruses tested in 2019 (proportion of donations positive by NAT were 0.0099% for human immunodeficiency virus [HIV], 0.0063% for hepatitis C virus [HCV], 0.0247% for hepatitis B virus [HBV], 0.0323% for hepatitis E virus [HEV], 0.0014% for West Nile virus [WNV] and 0.00005% for Zika virus [ZIKV]). Globally, over 3100 NAT-positive donations were identified as NAT yield or solely by NAT in 2019 and over 22,000 since the introduction of NAT, with HBV accounting for over half. NAT-positivity rate was higher in first-time donors for all viruses tested except WNV. During 2019, a small number of participants performed NAT for parasites (Trypanosoma cruzi, Babesia spp., Plasmodium spp.). CONCLUSION: This survey captures current use of blood donation NAT globally. There has been increased NAT usage over the last decade. It is clear that NAT contributes to improving blood transfusion safety globally; however, there is a need to overcome economic barriers for regions/countries not performing NAT.

Sequential administration of paricalcitol followed by IL-17 blockade for progressive refractory IgA nephropathy patients.

There is no established treatment for progressive IgA nephropathy refractory to steroids and immunosuppressant drugs (r-IgAN). Interleukin 17 (IL-17) blockade has garnered interest in immune-mediated diseases involving the gut-kidney axis. However, single IL-17A inhibition induced paradoxical effects in patients with Crohn's disease and some cases of de novo glomerulonephritis, possibly due to the complete Th1 cell response, along with the concomitant downregulation of regulatory T cells (Tregs). Seven r-IgAN patients were treated with at least six months of oral paricalcitol, followed by the addition of subcutaneous anti-IL-17A (secukinumab). After a mean follow-up of 28 months, proteinuria decreased by 71% (95% CI: 56-87), P < 0.001. One patient started dialysis, while the annual eGFR decline in the remaining patients [mean (95% CI)] was reduced by 4.9 mL/min/1.73 m2 (95% CI: 0.1-9.7), P = 0.046. Circulating Th1, Th17, and Treg cells remained stable, but Th2 cells decreased, modifying the Th1/Th2 ratio. Intriguingly, accumulation of circulating Th17.1 cells was observed. This novel sequential therapy appears to optimize renal advantages in patients with r-IgAN and elicit alterations in potentially pathogenic T helper cells.

A Systematic Review on Assessing Assessments: Unveiling Psychometric Properties of Instruments for Reactive Attachment Disorder and Disinhibited Social Engagement Disorder in Minors under Protective Measures.

BACKGROUND: Reactive attachment disorder (RAD) and disinhibited social engagement disorder (DSED) manifest in individuals facing attachment system challenges, particularly observed in minors under protective measures. The lack of standardized tools for assessing these difficulties and uncertainty about the most effective instruments from a psychometric perspective prompted this study. AIM: Using the COSMIN checklist, we systematically reviewed instruments assessing RAD, adhering to PRISMA. METHODOLOGY: Examined tools included the Disturbance Attachment Interview, Preschool Age Psychiatric Assessment, Relationship Patterns Questionnaire, Assessment of RAD and DSED, Development and Well-Being Assessment, and Reactive Attachment Disorder Questionnaire. RESULTS: Of the 10 articles analyzed, the results highlight a research emphasis on internal consistency and structural and construct validity, sidelining other properties. CONCLUSION: Most articles review structural validity and internal consistency. These measures are satisfactory but insufficiently evaluated. It is necessary to evaluate these tools using other indicators such as cross-cultural validity, measurement error, or responsiveness in adolescents under protective measures.

Design and characterization of an electrochemically-modulated membrane chromatography device.

Membrane separations offer a compelling alternative to traditional chromatographic methods by overcoming mass transport limitations. We introduce an additional degree of freedom in modulating membrane chromatography by using metalized membranes in a potential-driven process. Investigating the impact of a gold coating on membrane characteristics, the sputtered gold layer enhances the surface conductivity with stable electrochemical behavior. However, this comes at the expense of reduced permeability, wettability, and static binding capacity (∼ 474 µg g-1 of maleic acid). The designed device displayed a homogenous flow distribution, and the membrane electrodes exhibit predominantly capacitive behavior during potential application. Modulating the electrical potential during the adsorption and desorption phase strongly influenced the binding and elution behavior of anion-exchange membranes. Switching potentials between ±1.0 V vs. Ag/AgCl induces desorption, confirming the process principle. Elution efficiency reaches up to 58 % at -1.0 V vs. Ag/AgCl in the desorption phase without any alteration of the mobile phase. Increasing the potential perturbation ranging from +1.0 V to -1.0 V vs. Ag/AgCl resulted in reduced peak width and improved elution behavior, demonstrating the feasibility of electrochemically-modulated membrane chromatography. The developed process has great potential as a gentle and sustainable separation step in the biotechnological and chemical industry.

Isolation, Quantification, and Visualization of Extracellular Membrane Vesicles in Rhizobia Under Free-Living Conditions.

Rhizobia are a group of soil proteobacteria that are able to establish a symbiotic interaction with legumes. These bacteria are capable to fix atmospheric nitrogen into ammonia within specific plant root organs called nodules. The rhizobia-legume interaction is established by a complex molecular dialogue that starts with flavonoids exudated by the plant roots. In response, signaling molecules known as Nod factors (NFs) are secreted by the bacteria. These factors are sensed by specific plant receptors that trigger a downstream signaling cascade leading to rhizobium-specific intracellular colonization of the root hair via the formation of infection threads and the eventual development of nodules on roots. In these organs, rhizobia can fix nitrogen from the atmosphere for the plant in exchange for photosynthates and the appropriate environment for nitrogen fixation. Recently, it has been demonstrated that extracellular membrane vesicles (EMVs) produced by some rhizobia carry NFs. EMVs are proteolipidic structures that are secreted to the milieu from the bacterial membranes and are involved in several important biological processes, including intercellular communication. Thus far, little is known about rhizobia vesicles, and further studies are needed to understand their functions, including their role as transporting vessels of signaling molecules during the process of symbiosis. Here, we present a detailed protocol to isolate high-purity EMVs from free-living cultured rhizobia, test their integrity, and quantify their abundance.

Isolation of Rhizobial Extracellular Membrane Vesicles from Bacteroids.

Extracellular-membrane vesicles (EMVs) are spherical buds of the extracellular membrane, commonly produced by Gram-negative bacteria, known to mediate intricate inter-kingdom communication. In this context, comprehensive research dissecting the role of EMVs in one of the most complex nature-occurring molecular dialogues, rhizobium-legume symbiosis, has been so far neglected. During the different stages of the symbiotic process, rhizobia and their host plants establish a very specific and controlled intercellular trafficking of signal molecules. Thus, as conveyors of a broad range of molecules into the target cell, EMVs are gaining weight in the field. Here, we describe a detailed protocol to isolate EMVs from bacteroids of legume nodules, opening a new door for discovering new authors of the symbiotic process.

Patient-Reported Outcomes in Patients Undergoing Lumpectomy With and Without Defect Closure.

BACKGROUND: The effect of lumpectomy defect repair (a level 1 oncoplastic technique) on patient-reported breast satisfaction among patients undergoing lumpectomy has not yet been investigated. METHODS: Patients undergoing lumpectomy at our institution between 2018 and 2020 with or without repair of their lumpectomy defect during index operation, comprised our study population. The BREAST-Q quality-of-life questionnaire was administered preoperatively, and at 6 months, 1 year, and 2 years postoperatively. Satisfaction and quality-of-life domains were compared between those who did and did not have closure of their lumpectomy defect, and compared with surgeon-reported outcomes. RESULTS: A total of 487 patients met eligibility criteria, 206 (42%) had their partial mastectomy defect repaired by glandular displacement. Median breast volume, as calculated from the mammogram, was smaller in patients undergoing defect closure (826 cm3 vs. 895 cm3, p = 0.006). There were no statistically significant differences in satisfaction with breasts (SABTR), physical well-being of the chest (PWB-CHEST), or psychosocial well-being (PsychWB) scores between the two cohorts at any time point. While patients undergoing defect closure had significantly higher sexual well-being (SexWB) scores compared with no closure (66 vs. 59, p = 0.021), there were no predictors of improvement in SexWB scores over time on multivariable analysis. Patients' self-reported scores positively correlated with physician-reported outcomes. CONCLUSIONS: Despite a larger lumpectomy-to-breast volume ratio among patients undergoing defect repair, satisfaction was equivalent among those whose defects were or were not repaired at 2 years postsurgery. Defect repair was associated with clinically relevant improvement in patient-reported sexual well-being.

Examining Race and Patient-Reported Outcomes After Contralateral Prophylactic Mastectomy with Reconstruction.

BACKGROUND: Little is known regarding racial differences in satisfaction and quality of life (QOL) after contralateral prophylactic mastectomy (CPM). In this study, we aim to characterize associations between race, and postoperative satisfaction and well-being, utilizing the validated BREAST-Q patient-reported outcome measure. PATIENTS AND METHODS: Patients were eligible if they were diagnosed with stage 0-III unilateral breast cancer and underwent mastectomy with immediate reconstruction at our institution between 2016 and 2022. BREAST-Q surveys were administered in routine clinical care preoperatively and postoperatively to assess QOL. We assessed whether the relationship between race, and domains of satisfaction with breasts and psychosocial well-being differed by receipt of CPM compared with unilateral mastectomy at 6 months, 1 year, 2 years, and 3 years following reconstruction. RESULTS: Of 3334 women, 2040 (61%) underwent unilateral mastectomy and 1294 (39%) underwent CPM. Compared with White and Asian women who received CPM, Black women who underwent CPM were more likely to have higher BMI (p < 0.001), undergo autologous reconstruction (p = 0.006), and receive postmastectomy radiation (PMRT) (p < 0.001). There was no association between race and domains of satisfaction of breasts or psychosocial well-being for women who underwent unilateral mastectomy (p = 0.6 and p > 0.9, respectively) or CPM (p = 0.8 and p = 0.9, respectively). PMRT was negatively associated with both satisfaction with breasts (p < 0.001) and psychosocial well-being (p = 0.007). CONCLUSIONS: Differences in satisfaction with breasts and psychosocial well-being at 3-year follow-up were not associated with race but rather treatment variables, particularly the receipt of PMRT. Further investigations with a larger and more diverse population are needed to validate these findings.

Financial influence on global risks of zoonotic emerging and re-emerging diseases: an integrative analysis.

BACKGROUND: Emerging and re-emerging infectious diseases (EIDs), such as Ebola virus disease and highly pathogenic influenza, are serious threats to human health and wellbeing worldwide. The financial sector has an important, yet often ignored, influence as owners and investors in industries that are associated with anthropogenic land-use changes in ecosystems linked to increased EIDs risks. We aimed to analyse financial influence associated with EIDs risks that are affected by anthropogenic land-use changes. We also aimed to provide empirical assessments of such influence to help guide engagements by governments, private organisations, and non-governmental organisations with the financial sector to advance a planetary health agenda. METHODS: For this integrative analysis, we identified regions in the world where there was evidence of a connection between EIDs and anthropogenic land-use changes between Nov 9, 1999, and Oct 25, 2021, through a targeted literature review of academic literature and grey literature to identify evidence of drivers of anthropogenic land-use change and their association with commodity production in these regions. We only included publications in English that showed a connection between deforestation and the production of one or more commodities. Publications merely describing spatial or temporal land-use change dynamics (eg, a reduction of forest or an increase of palm-oil plantations) were excluded. As we were assessing financial influence on corporate activities through ownership specifically, we focused our analysis on publicly listed companies. Equity data and data about ownership structure were extracted from Orbis, a company information database. We assessed financial influence by identifying financial entities with the largest equity ownership, descriptively mapping transboundary connections between investors and publicly listed companies. FINDINGS: 227 public and private companies operating in five economic sectors (ie, production of palm oil, pulp and wood products, cocoa, soybeans, and beef) between Dec 15, 2020, and March 8, 2021, were identified. Of these 227, 99 (44%) were publicly listed companies, with 2310 unique shareholders. These publicly listed companies operated in six geographical regions, resulting in nine case-study regions. 54 (55%) companies with complete geographical information were included in the countries network. Four financial entities (ie, Dimensional, Vanguard, BlackRock, and Norway's sovereign wealth fund) each had ownership in 39 companies or more in three of the case-study regions (ie, north America, east Asia, and Europe). Four large US-based asset managers (ie, Vanguard, BlackRock, T Rowe Price, and State Street) were the largest owners of publicly listed companies in terms of total equity size, with ownership amounts for these four entities ranging from US$8 billion to $21 billion. The specific patterns of cross-national ownership depended on the region of interest; for example, financial influence on EIDs risks that was associated with commodity production in southeast and east Asia came from not only global asset managers but also Malaysian, Chinese, Japanese, and Korean financial entities. India, Brazil, the USA, Mexico, and Argentina were the countries towards which investments were most directed. INTERPRETATION: Although commodity supply chains and financial markets are highly globalised, a small number of investors and countries could be viewed as disproportionally influential in sectors that increase EIDs risks. Such financial influence could be used to develop and implement effective policies to reduce ecological degradation and mitigate EIDs risks and their effects on population health. FUNDING: Formas and Networks of Financial Rupture-how cascading changes in the climate and ecosystems could impact on the financial sector.

Eficiência clínica de fios de polidioxanona no tratamento da flacidez tissular abdominal pós-parto: relato de caso / Clinical efficiency of polydioxanone threads in the treatment of postpartum abdominal tissue flaccidity: case report

Este estudo relata um caso de flacidez abdominal após 3 gestações no qual foi utilizada a técnica de fios de polidioxanona (PDO) lisos e espiculados, técnica ainda não descrita na literatura paratratarestaqueixa.Apacientefoiacompanhadapor90dias,ehouvemelhoradaabertura da prega umbilical, do tônus da pele, de densidade dérmica e da flacidez tissular após 60 dias. Neste período, a paciente declarou estar totalmente satisfeita e foiestabelecidaaaltadotratamento.Comestepresenterelatodecasopodemosconcluirquea terapia combinada de fios de PDO parafusos e fios de PDO espiculados (Sculpt®) apresentam resultados muito expressivos em relação a qualidade da pele promovendo melhora visível na flacidez tissular

Thisstudyreportsacaseofabdominalflaccidityafterthreepregnancies,inwhichthetechnique ofsmoothandspiculatedpolydioxanonethreadswasused,atechniquenotyetdescribedinthe literature to treat this complaint. The patient was followed up for 90 days, but there was an improvement in the opening of the umbilical fold, skin tone, increase in dermal density and especially a reduction in tissue flaccidity in 60 days. During this period, the patient declared thatshewascompletelysatisfied,anddischargefromtreatmentwasestablished.Withthiscase report, we can conclude that the combined therapy of PDO threads screws and PDO threads spiculated (Sculpt®) presentvery expressive results about the quality of the skin, promoting a visible improvement in tissue flaccidity

Reactive Attachment Disorder and Its Relationship to Psychopathology: A Systematic Review.

This study aimed to determine, through a systematic review, the relationship between Reactive Attachment Disorder (RAD) and the presence of psychopathology in children and adolescents, and to determine the existence of differences in terms of internalising and externalising psychological problems between the RAD group and groups with other disorders or with typical development. Following the PRISMA methodology, a search was carried out in the Web of Science, PubMed and Scopus databases. The search yielded 770 results, of which only 25 met the inclusion criteria. The results indicate a relationship between the presence of RAD and/or disinhibited social engagement disorder (DSED), with the presence of internalising and externalising problems. These difficulties are more present in children with RAD compared to children without personal difficulties, or children with DSED, children with autism, children with intellectual disabilities or children with hyperactivity. It can be concluded that the presence of RAD has negative consequences on the mental health of children and adolescents, with these being greater in the inhibited group than in the disinhibited group, and with respect to children with autism or hyperactivity.

Mechanical Disruption of the Inner Limiting Membrane In Vivo Enhances Targeting to the Inner Retina.

Purpose: To evaluate the effects of mechanical disruption of the inner limiting membrane (ILM) on the ability to target interventions to the inner neurosensory retina in a rodent model. Our study used an animal model to gain insight into the normal physiology of the ILM and advances our understanding of the effects of mechanical ILM removal on the viral transduction of retinal ganglion cells and retinal ganglion cell transplantation. Methods: The ILM in the in vivo rat eye was disrupted using mechanical forces applied to the vitreoretinal interface. Immunohistology and electron microscopy were used to verify the removal of the ILM in retina flatmounts and sections. To assess the degree to which ILM disruption enhanced transvitreal access to the retina, in vivo studies involving intravitreal injections of adeno-associated virus (AAV) to transduce retinal ganglion cells (RGCs) and ex vivo studies involving co-culture of human stem cell-derived RGCs (hRGCs) on retinal explants were performed. RGC transduction efficiency and transplanted hRGC integration with retinal explants were evaluated by immunohistology of the retinas. Results: Mechanical disruption of the ILM in the rodent eye was sufficient to remove the ILM from targeted retinal areas while preserving the underlying retinal nerve fiber layer and RGCs. Removal of the ILM enhanced the transduction efficiency of intravitreally delivered AAV threefold (1380.0 ± 290.1 vs. 442.0 ± 249.3 cells/mm2; N = 6; P = 0.034). Removal of the ILM was also sufficient to promote integration of transplanted RGCs within the inner retina. Conclusions: The ILM is a barrier to transvitreally delivered agents including viral vectors and cells. Mechanical removal of the ILM is sufficient to enhance access to the inner retina, improve viral transduction efficiencies of RGCs, and enhance cellular integration of transplanted RGCs with the retina.

Response to physical activity of females with multiple sclerosis throughout the menstrual cycle: a protocol for a randomised crossover trial (EMMA Project).

The relationship between multiple sclerosis (MS) and females is a crucial aspect in the development of the disease, with the ovarian hormonal cycle being a sensitive stage, especially in females with relapsing-remitting multiple sclerosis. The objectives of the study are to identify moderating variables that modify satisfaction with physical activity practice throughout the menstrual cycle (MC) in females in or out of their MC, during high-intensity interval training (HIIT) and strength training sessions and to compare the acute effects of different types of physical activity sessions in females with and without MS. This protocol is the methodology used in the EMMA Study, a randomised, single-blind crossover trial study conducted in females with MS who were matched 1:1, based on age, lifestyle factors and country of residence, with females without MS, to analyse the effect of physical activity practice on satisfaction, functionality, fatigue and inflammatory profile through their MC. Participants will visit the facilities approximately 10 times (4 preliminary familiarisation visits and 6 visits to carry out a physical activity session in each phase of the MC) for 3-4 months. A total sample of 30 females (15 females without MS and 15 with MS) is necessary for the study. The evaluation will comprise clinical, nutritional and psychological interviews, including different variables. It is hypothesised during the luteal phase, females with MS are expected to exhibit different acute responses to HIIT and strength training sessions as compared with females without the disease. Before starting the study, all participants will read and sign an informed consent form. Trial registration number: This research protocol is registered with ClinicalTrials.gov to ensure transparency and accessibility of study information (NCT06105463). The university's ethics committee number for this study is UALBIO2022/048.

Effects of Cycling on Spine: A Case-Control Study Using a 3D Scanning Method.

BACKGROUND: Few studies have investigated the effects of adopting a specific and prolonged posture on cyclists. This study aimed to evaluate the upright spine in a sample of recreational cyclists and compare it with a sample of non-cyclists, though still athletes, through a 3D scanning method. METHODS: Forty-eight participants were enrolled in this observational study. The sample consisted of 25 cyclists for the cycling group and 23 non-cyclist athletes for the control group. The Spine3D device (Sensor Medica, Guidonia Montecelio, Rome, Italy) was used to evaluate the spine of the participants in both groups. RESULTS: The results showed significantly greater spine inclination in the cycling group compared to the control group (p < 0.01). Furthermore, there was a significant decrease in lumbar lordosis in the cycling group compared to the control group (p < 0.01). CONCLUSIONS: This case-control study raises the possibility that the onset of lower back pain in cyclists may be due to a reduction in lumbar lordosis. Furthermore, this study demonstrated that the Spine3D device can be used in sports to monitor the spine of athletes to prevent and reduce musculoskeletal deficits.