Bone marrow niches for hematopoietic stem cells.

Hematopoietic stem cells (HSCs) are the cornerstone of the hematopoietic system. HSCs sustain the continuous generation of mature blood derivatives while self-renewing to preserve a relatively constant pool of progenitors throughout life. Yet, long-term maintenance of functional HSCs exclusively takes place in association with their native tissue microenvironment of the bone marrow (BM). HSCs have been long proposed to reside in fixed and identifiable anatomical units found in the complex BM tissue landscape, which control their identity and fate in a deterministic manner. In the last decades, tremendous progress has been made in the dissection of the cellular and molecular fabric of the BM, the structural organization governing tissue function, and the plethora of interactions established by HSCs. Nonetheless, a holistic model of the mechanisms controlling HSC regulation in their niche is lacking to date. Here, we provide an overview of our current understanding of BM anatomy, HSC localization, and crosstalk within local cellular neighborhoods in murine and human tissues, and highlight fundamental open questions on how HSCs functionally integrate in the BM microenvironment.

Insulin resistance in nonobese type 2 diabetic Goto Kakizaki rats is associated with a proinflammatory T lymphocyte profile.

Goto-Kakizaki (GK) rats develop a well-defined insulin resistance (IR) and type 2 diabetes mellitus (T2DM) without presenting obesity. The lymphocyte profile in nonobese diabetic conditions is not yet characterized. Therefore, GK rats were chosen to explore T lymphocyte (TL) dynamics at various stages (21, 60, and 120 days) compared to Wistar rats. GK rats exhibit progressive disruption of glucose regulation, with early glucose intolerance at 21 days and reduced insulin sensitivity at 60 days, confirming IR. Glucose transporter 1 (GLUT1) expression was consistently elevated in GK rats, suggesting heightened TL activation. T-regulatory lymphocyte markers diminished at 21 days. However, GK rats showed increased Th1 markers and reduced Gata-3 expression (crucial for Th2 cell differentiation) at 120 days. These findings underscore an early breakdown of anti-inflammatory mechanisms in GK rats, indicating a proinflammatory TL profile that may worsen chronic inflammation in T2DM.

The link between alterations in circadian rhythms and lipid metabolism in bipolar disorder: the lipid droplets hypothesis.

Bipolar disorder (BD) is a neuropsychiatric illness characterized by recurrent episodes of mania and depression, leading to profound cognitive and functional impairments, psychiatric and metabolic comorbidities, and substantial healthcare costs. Due to its complex nature and absence of specific biomarkers, BD presents significant daily challenges for clinicians. Therefore, advancing our understanding of BD pathophysiology is essential to identify novel diagnostic biomarkers and potential therapeutic targets. Although its neurobiology remains unclear, disruption of circadian rhythms and lipid alterations have emerged as key hallmarks of BD. As essential components of the brain, lipids play a pivotal role in regulating synaptic activity and neuronal development. Thus, alterations in brain lipids may contribute to the neuroanatomical changes and reduced neuroplasticity observed in BD. The levels of toxic lipids inside the cell are buffered by lipid droplets that regulate the storage of neutral lipids. These dynamic organelles adapt to cellular needs, and their dysregulated accumulation has been linked to various pathological conditions. Notably, lipid droplets and various lipid classes display rhythmic oscillations throughout the 24-hour cycle, suggesting a link between lipid metabolism, circadian rhythms and lipid droplets. In this review, we explore the impairment of circadian rhythms and lipid metabolism in BD, along with evidence demonstrating that circadian clocks regulate the accumulation of lipid droplets. Importantly, we propose the "lipid droplets hypothesis for BD" that considers that the compromised lipid metabolism in BD is intimately associated with alterations in the lipid droplets homeostasis, which can be driven by disturbances in the circadian clocks.

Comparative study between high-fidelity simulation and medium-fidelity simulation in decision-making of nursing students: experimental study.

OBJECTIVE: to compare the decision-making of Nursing students, before and after theoretical training on basic life support, using the practice of high-fidelity simulation and medium-fidelity simulation. METHOD: an experimental study was developed, pre- and post-test type, with quantitative, descriptive and inferential analysis, with theoretical training on basic life support and clinical simulation practices, and with evaluation of knowledge and decision-making of Nursing students, at three different moments - before the simulation scenario (T0), after the simulation scenario (T1) and after clinical teaching (T2). RESULTS: 51 students participated in the research, with an average age of 20.25±3.804, of which 92.2% were female. Statistically significant differences (F=6.47; p=0.039) were evident regarding the definition of the problem and development of objectives in decision-making in the experimental group. CONCLUSION: Nursing students demonstrate an adequate level of knowledge and a good decision-making process, based on the most current instruments produced by scientific evidence, in clinical simulation scenarios in basic life support, and this innovative methodology should be deepened in the Nursing teaching. HIGHLIGHTS: (1) Clinical simulation promotes good decision-making of Nursing students.(2) Students demonstrated adequate knowledge about basic life support.(3) Knowledge and practice define the fidelity of clinical simulation.(4) Basic life support can be developed by high-fidelity simulation.

An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes.

In recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate fine neuronal subtypes are still limited. Here, we performed systematic analysis of single cell genomic data to identify enhancer candidates for each of the cortical interneuron subtypes. We established a set of enhancer-AAV tools that are highly specific for distinct cortical interneuron populations and striatal cholinergic neurons. These enhancers, when used in the context of different effectors, can target (fluorescent proteins), observe activity (GCaMP) and manipulate (opto- or chemo-genetics) specific neuronal subtypes. We also validated our enhancer-AAV tools across species. Thus, we provide the field with a powerful set of tools to study neural circuits and functions and to develop precise and targeted therapy.

Relationship between season and spermatozoa traits of captive-reared agoutis from Brazilian semiarid.

For the development of efficient management and conservation strategies for wild rodent species, understanding the aspects related to their reproduction, including the interaction of this physiological function with the environment, is essential. This study aimed to evaluate the impacts of weather changes derived from a semiarid region's dry and rainy seasons on the epididymal sperm characteristics of red-rumped agouti (Dasyprocta leporina), a histricognath rodent, still little studied, which inhabits the Brazilian Caatinga. The sperm from the epididymal cauda of 14 agoutis were collected, seven individuals per season (dry and rainy). Samples were evaluated for kinetic parameters, membrane structural and functional integrity, mitochondrial activity, morphology, and morphometry. The environmental variables were measured: maximum air temperature, relative humidity, wind speed, solar radiation, and the total rainfall for dry and rainy seasons were, respectively, 36.2 and 34.1 °C, 66.8 and 80.1%, 4.0 and 1.9 m/s, 527.3 and 441.8 W/m2, and 0.2 and 517.7 mm. There were strong correlations between some sperm parameters and environmental variables, mainly those related to the acquisition of sperm mobility. Sperm concentration and the number of sperm collected were higher in the dry (1028.7 sperm/mL × 106 and 1361.2 × 106 sperm) than in the rainy season (758.9 sperm × 106/mL and 714.6 sperm × 106). During the rainy season, there were fewer sperm defects, higher sperm metrics, and higher membrane structural integrity with mitochondrial activity. Regarding motility patterns, the increases during the rainy season stand out in total and progressive motility, VAP, VSL, VCL, and subpopulations of rapid sperm. In summary, our results suggest that the adverse climatic conditions of the dry season in the semiarid region, mainly high solar radiation and temperature, considerably impair the epididymal sperm quality of red-rumped agoutis. On the contrary, the largest amount of sperm was obtained during this season, probably due to compensatory and adaptive mechanisms of the species to enable its reproduction throughout the year.

Impact of allergic rhinitis control on work productivity and costs: a real-world data MASK-air study.

BACKGROUND: Allergic rhinitis (AR) has a substantial socioeconomic impact associated with impaired work productivity. OBJECTIVE: To study the impact of AR on work productivity and estimate the corresponding indirect costs for 40 countries. METHODS: We conducted a cross-sectional study using direct patient data from the MASK-air® app on users with self-reported AR. We used the Work Productivity and Activity Impairment Questionnaire: Allergy Specific to measure the impact of AR on work productivity (presenteeism and absenteeism). Weekly indirect costs were estimated per country, for each level of rhinitis control and considering patients with and without asthma. RESULTS: We assessed data from 677 weeks (364 patients), 280 of which were reported by patients with asthma. Regarding presenteeism, the median impact of AR in weeks of poor disease control was 60.7% (P25-P75=24.9-74.2%), while partial and good disease control were respectively associated with an impact of 25.0% (P25-P75=12.1-42.4%) and 4.4% (P25-75=0.8-12.9%). In poorly-controlled weeks, presenteeism was associated with indirect costs ranging from 65.7 US Dollars purchase power parity (US$ PPPs) (P25-P75=29.2-143.2) in Brazil to 693.6 US$ PPP (P25-P75=405.2-1094.9) in Iceland. Median absenteeism per week was of 0% for all levels of rhinitis control. Patients with AR+asthma showed higher overall work impairment than patients with AR alone, particularly in poorly-controlled weeks (median work impairment in AR alone=39.1% [P25-P75=12.5-71.9%]; median work impairment in AR+asthma=68.4% [P25-P75=54.6-80.2%]). CONCLUSION: Poor AR control was associated with decreased work productivity and increased indirect costs, particularly in patients with AR+asthma. The estimates from this study underpin the economic burden of AR.

Nanoemulsions of essential oils against multi-resistant microorganisms: An integrative review.

Microbial resistance to drugs continues to be a global public health issue that demands substantial investment in research and development of new antimicrobial agents. Essential oils (EO) have demonstrated satisfactory and safe antimicrobial action, being used in pharmaceutical, cosmetic, and food formulations. In order to improve solubility, availability, and biological action, EO have been converted into nanoemulsions (NE). This review identified scientific evidence corroborating the antimicrobial action of nanoemulsions of essential oils (NEEO) against antibiotic-resistant pathogens. Using integrative review methodology, eleven scientific articles evaluating the antibacterial or antifungal assessment of NEEO were selected. The synthesis of evidence indicates that NEEO are effective in combating multidrug-resistant microorganisms and in the formation of their biofilms. Factors such as NE droplet size, chemical composition of essential oils, and the association of NE with antibiotics are discussed. Furthermore, NEEO showed satisfactory results in vitro and in vivo evaluations against resistant clinical isolates, making them promising for the development of new antimicrobial and antivirulence drugs.

Current insights into the effects of cationic biocides exposure on Enterococcus spp.

Cationic biocides (CBs), such as quaternary ammonium compounds and biguanides, are critical for controlling the spread of bacterial pathogens like Enterococcus spp., a leading cause of multidrug-resistant healthcare-associated infections. The widespread use of CBs in recent decades has prompted concerns about the potential emergence of Enterococcus spp. populations exhibiting resistance to both biocides and antibiotics. Such concerns arise from their frequent exposure to subinhibitory concentrations of CBs in clinical, food chain and diverse environmental settings. This comprehensive narrative review aimed to explore the complexity of the Enterococcus' response to CBs and of their possible evolution toward resistance. To that end, CBs' activity against diverse Enterococcus spp. collections, the prevalence and roles of genes associated with decreased susceptibility to CBs, and the potential for co- and cross-resistance between CBs and antibiotics are reviewed. Significant methodological and knowledge gaps are identified, highlighting areas that future studies should address to enhance our comprehension of the impact of exposure to CBs on Enterococcus spp. populations' epidemiology. This knowledge is essential for developing effective One Health strategies that ensure the continued efficacy of these critical agents in safeguarding Public Health.

Exploring Disulfiram's Anticancer Potential: PLGA Nano-Carriers for Prolonged Drug Delivery and Potential Improved Therapeutic Efficacy.

Disulfiram (DS) has been shown to have potent anti-cancer activity; however, it is also characterised by its low water solubility and rapid metabolism in vivo. Biodegradable polylactic-co-glycolic acid (PLGA) polymers have been frequently employed in the manufacturing of PLGA nano-carrier drug delivery systems. Thus, to develop DS-loaded PLGA nanoparticles (NPs) capable of overcoming DS's limitations, two methodologies were used to formulate the NPs: direct nanoprecipitation (DNP) and single emulsion/solvent evaporation (SE), followed by particle size reduction. The DNP method was demonstrated to produce NPs of superior characteristics in terms of size (151.3 nm), PDI (0.083), charge (-37.9 mV), and loading efficiency (65.3%). Consequently, NPs consisting of PLGA and encapsulated DS coated with mPEG2k-PLGA at adjustable ratios were prepared using the DNP method. Formulations were then characterised, and their stability in horse serum was assessed. Results revealed the PEGylated DS-loaded PLGA nano-carriers to be more efficient; hence, in-vitro studies testing these formulations were subsequently performed using two distinct breast cancer cell lines, showing great potential to significantly enhance cancer therapy.

Lemierre Syndrome: Clinical Challenges And The Anticoagulation Dilemma In Adolescent Care.

Lemierre syndrome is a rare, life-threatening condition characterized by an acute otorhinolaryngologic infection with septic thrombophlebitis of the internal jugular vein and septic embolism, particularly to the lungs. We describe a case of a previously healthy 15-year-old female patient who initially presents fever and odynophagia but quickly develops neck and pleuritic chest pain. Computed tomography was performed and the radiological findings confirmed the diagnosis of a Lemierre syndrome. She was managed with antibiotics, anticoagulant for three days and symptomatic treatment, with a gradually improving condition. After 17 days of hospitalisation, due to reappearance of pleuritic pain, a new imaging assessment was performed and showed additional septic emboli in the lungs, which prompted the reintroduction of anticoagulant therapy. Awareness of the existence of this syndrome is essential to ensure a radiological evaluation with computed tomography and thus timely diagnosis and treatment.

Climate correlates of bluetongue incidence in southern Portugal.

Model forecasts of the spatiotemporal occurrence dynamics of diseases are necessary and can help understand and thus manage future disease outbreaks. In our study, we used ecological niche modelling to assess the impact of climate on the vector suitability for bluetongue disease, a disease affecting livestock production with important economic consequences. Specifically, we investigated the relationship between the occurrence of bluetongue outbreaks and the environmental suitability of each of the four vector species studied. We found that the main vector for bluetongue disease, Culicoides imicola, a typically tropical and subtropical species, was a strong predictor for disease outbreak occurrence in a region of southern Portugal from 2004 to 2021. The results highlight the importance of understanding the climatic factors that might influence vector presence to help manage infectious disease impacts. When diseases impact economically relevant species, the impacts go beyond mortality and have important economic consequences.

Legionella colonization and 3D spatial location within a Pseudomonas biofilm.

Biofilms are known to be critical for Legionella settlement in engineered water systems and are often associated with Legionnaire's Disease events. One of the key features of biofilms is their heterogeneous three-dimensional structure which supports the establishment of microbial interactions and confers protection to microorganisms. This work addresses the impact of Legionella pneumophila colonization of a Pseudomonas fluorescens biofilm, as information about the interactions between Legionella and biofilm structures is scarce. It combines a set of meso- and microscale biofilm analyses (Optical Coherence Tomography, Episcopic Differential Interference Contrast coupled with Epifluorescence Microscopy and Confocal Laser Scanning Microscopy) with PNA-FISH labelled L. pneumophila to tackle the following questions: (a) does the biofilm structure change upon L. pneumophila biofilm colonization?; (b) what happens to L. pneumophila within the biofilm over time and (c) where is L. pneumophila preferentially located within the biofilm? Results showed that P. fluorescens structure did not significantly change upon L. pneumophila colonization, indicating the competitive advantage of the first colonizer. Imaging of PNA-labelled L. pneumophila showed that compared to standard culture recovery it colonized to a greater extent the 3-day-old P. fluorescens biofilms, presumably entering in VBNC state by the end of the experiment. L. pneumophila was mostly located in the bottom regions of the biofilm, which is consistent with the physiological requirements of both bacteria and confers enhanced Legionella protection against external aggressions. The present study provides an expedited methodological approach to address specific systematic laboratory studies concerning the interactions between L. pneumophila and biofilm structure that can provide, in the future, insights for public health Legionella management of water systems.

Effects of 34 Weeks of Military Service on Body Composition and Physical Fitness in Military Cadets of Angola.

Military personnel need physical fitness to effectively carry out operational military activities within their specific field of operation. This research investigates the effects of a 34-week training program on Angolan cadets' body composition, muscle strength, and cardiorespiratory fitness. Seventy-four volunteer recruits, aged 18 to 26 years, were monitored during their eight-month military service, following an exercise program protocol comprising 12 weeks of strength training followed by 24 weeks of endurance training. Anthropometric variables, including body mass, body mass index, and fat mass, were assessed, along with cardiorespiratory fitness (VO2max), sprint performance, countermovement jump (CMJ), medicine ball throw, push-ups, and curl-ups. The physical training protocol encompassed running sessions, strength exercises, agility drills, and flexibility exercises. The initial assessment revealed gender differences in various parameters such as body mass, body fat percentage, VO2max, sprinting, countermovement jump (CMJ), medicine ball throw, and push-ups. Following the training program, changes were observed in all variables (effect size between 0.48 and 2.33, p < 0.01) for the participants. Significant interactions (sex × time) were found in body mass (F = 5.18, p = 0.03, ηp2 = 0.06), body fat percentage (F = 5.31, p < 0.01, ηp2 = 0.14), and medicine ball throw (F = 10.84, p < 0.01, ηp2 = 0.13). Specifically, males exhibited a greater reduction in body mass (females: 2.70%, males: 3.47%, p < 0.05) and a substantial improvement in ball throwing performance (females: 7.74%, males: 11.47%, p < 0.01), while females experienced a greater reduction in fat mass (females: 5.34%, males: 3.15%, p < 0.01). The physical training regimen effectively influenced body composition, particularly in enhancing strength performance among males. The integration of exercise programs with military service led to a notable reduction in fat tissue and an increase in lean tissue. Hence, the development of tailored training protocols is imperative to enhance the physical capacity and overall health of military recruits, considering sex-specific characteristics and physical attributes.

A 3D bioreactor model to study osteocyte differentiation and mechanobiology under perfusion and compressive mechanical loading.

Osteocytes perceive and process mechanical stimuli in the lacuno-canalicular network in bone. As a result, they secrete signaling molecules that mediate bone formation and resorption. To date, few three-dimensional (3D) models exist to study the response of mature osteocytes to biophysical stimuli that mimic fluid shear stress and substrate strain in a mineralized, biomimetic bone-like environment. Here we established a biomimetic 3D bone model by utilizing a state-of-art perfusion bioreactor platform where immortomouse/Dmp1-GFP-derived osteoblastic IDG-SW3 cells were differentiated into mature osteocytes. We evaluated proliferation and differentiation properties of the cells on 3D microporous scaffolds of decellularized bone (dBone), poly(L-lactide-co-trimethylene carbonate) lactide (LTMC), and beta-tricalcium phosphate (ß-TCP) under physiological fluid flow conditions over 21 days. Osteocyte viability and proliferation were similar on the scaffolds with equal distribution of IDG-SW3 cells on dBone and LTMC scaffolds. After seven days, the differentiation marker alkaline phosphatase (Alpl), dentin matrix acidic phosphoprotein 1 (Dmp1), and sclerostin (Sost) were significantly upregulated in IDG-SW3 cells (p = 0.05) on LTMC scaffolds under fluid flow conditions at 1.7 ml/min, indicating rapid and efficient maturation into osteocytes. Osteocytes responded by inducing the mechanoresponsive genes FBJ osteosarcoma oncogene (Fos) and prostaglandin-endoperoxide synthase 2 (Ptgs2) under perfusion and dynamic compressive loading at 1 Hz with 5 % strain. Together, we successfully created a 3D biomimetic platform as a robust tool to evaluate osteocyte differentiation and mechanobiology in vitro while recapitulating in vivo mechanical cues such as fluid flow within the lacuno-canalicular network. STATEMENT OF SIGNIFICANCE: This study highlights the importance of creating a three-dimensional (3D) in vitro model to study osteocyte differentiation and mechanobiology, as cellular functions are limited in two-dimensional (2D) models lacking in vivo tissue organization. By using a perfusion bioreactor platform, physiological conditions of fluid flow and compressive loading were mimicked to which osteocytes are exposed in vivo. Microporous poly(L-lactide-co-trimethylene carbonate) lactide (LTMC) scaffolds in 3D are identified as a valuable tool to create a favorable environment for osteocyte differentiation and to enable mechanical stimulation of osteocytes by perfusion and compressive loading. The LTMC platform imitates the mechanical bone environment of osteocytes, allowing the analysis of the interaction with other cell types in bone under in vivo biophysical stimuli.

Neuropsychological profile in tuberous sclerosis complex: a study of clinical and cognitive variables in a cohort from Brazil.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder with a wide clinical, cognitive, and behavioral expressivity. OBJECTIVE: To assess the neuropsychological profile of individuals clinically diagnosed with TSC and the factors that could significantly impact their cognitive development. METHODS: A total of 62 individuals with ages ranging from 3 to 38 years were followed up in a tertiary attention hospital in Southern Brazil, and they were assessed using a standard battery and the Vineland Adaptive Behavior Scales, when intellectual disability was observed. RESULTS: History of epilepsy was found in 56 participants (90.3%), and 31 (50%) presented an intellectual disability. Among the other half of TSC individuals without intellectual disability, 8 (12.9%) presented borderline classification, 20 (32.2%) presented average scores, and 3 (4.8%) were above average. In total, 17 participants (27.4%) fulfilled the diagnostic criteria for autism spectrum disorder. The results of the multiple linear regression analysis suggested that seizures, age at diagnosis, visual perception, and general attention significantly impact cognitive performance indexes. CONCLUSION: The present study suggests that the occurrence of epileptic seizures and older age at diagnosis contribute to higher impairment in the domains of cognitive development, underlining the importance of early diagnosis and the prevention of epileptic seizures or their rapid control. The development of attentional skills, visual perception, and executive functions must be followed up.

ANTECEDENTES: O complexo da esclerose tuberosa (CET) é uma doença genética autossômica dominante com ampla expressividade clínica, cognitiva e comportamental. OBJETIVO: Avaliar o perfil neuropsicológico de indivíduos com diagnóstico clínico de CET e os fatores que poderiam impactar significativamente o seu desenvolvimento cognitivo. MéTODOS: Ao todo, 62 indivíduos com idades entre 3 e 38 anos foram acompanhados em um hospital terciário do Sul do Brasil e avaliados por meio de uma bateria padrão e das Escalas de Comportamento Adaptativo Vineland, quando observada deficiência intelectual. RESULTADOS: Encontrou-se histórico de epilepsia em 56 participantes (90,3%) e de deficiência intelectual em 31 (50%). Quanto à outra metade dos indivíduos com CET sem deficiência intelectual, 8 (12,9%) apresentaram classificação limítrofe, 20 (32,2%) apresentaram pontuações médias e 3 (4,8%) estavam acima da média. No total, 17 participantes (27,4%) preenchiam os critérios diagnósticos para o transtorno do espectro autista. Os resultados da análise de regressão linear múltipla sugeriram que as crises epilépticas, a idade ao diagnóstico, a percepção visual e a atenção geral impactam significativamente os índices de desempenho cognitivo. CONCLUSãO: Este estudo sugere que a ocorrência de crises epilépticas e a maior idade ao diagnóstico contribuem para um maior comprometimento nos domínios do desenvolvimento cognitivo, e destaca-se a importância do diagnóstico precoce e da prevenção das crises epilépticas ou do seu rápido controle. O desenvolvimento de habilidades de atenção, percepção visual e funções executivas deve ser acompanhado.

The two alternative NADH:quinone oxidoreductases from Staphylococcus aureus: two players with different molecular and cellular roles.

Staphylococcus aureus is an opportunistic pathogen that has emerged as a major public health threat due to the increased incidence of its drug resistance. S. aureus presents a remarkable capacity to adapt to different niches due to the plasticity of its energy metabolism. In this work, we investigated the energy metabolism of S. aureus, focusing on the alternative NADH:quinone oxidoreductases, NDH-2s. S. aureus presents two genes encoding NDH-2s (NDH-2A and NDH-2B) and lacks genes coding for Complex I, the canonical respiratory NADH:quinone oxidoreductase. This observation makes the action of NDH-2s crucial for the regeneration of NAD+ and, consequently, for the progression of metabolism. Our study involved the comprehensive biochemical characterization of NDH-2B and the exploration of the cellular roles of NDH-2A and NDH-2B, utilizing knockout mutants (Δndh-2a and Δndh-2b). We show that NDH-2B uses NADPH instead of NADH, does not establish a charge-transfer complex in the presence of NADPH, and its reduction by this substrate is the catalytic rate-limiting step. In the case of NDH-2B, the reduction of the flavin is inherently slow, and we suggest the establishment of a charge transfer complex between NADP+ and FADH2, as previously observed for NDH-2A, to slow down quinone reduction and, consequently, prevent the overproduction of reactive oxygen species, which is potentially unnecessary. Furthermore, we observed that the lack of NDH-2A or NDH-2B impacts cell growth, volume, and division differently. The absence of these enzymes results in distinct metabolic phenotypes, emphasizing the unique cellular roles of each NDH-2 in energy metabolism.IMPORTANCEStaphylococcus aureus is an opportunistic pathogen, posing a global challenge in clinical medicine due to the increased incidence of its drug resistance. For this reason, it is essential to explore and understand the mechanisms behind its resistance, as well as the fundamental biological features such as energy metabolism and the respective players that allow S. aureus to live and survive. Despite its prominence as a pathogen, the energy metabolism of S. aureus remains underexplored, with its respiratory enzymes often escaping thorough investigation. S. aureus bioenergetic plasticity is illustrated by its ability to use different respiratory enzymes, two of which are investigated in the present study. Understanding the metabolic adaptation strategies of S. aureus to bioenergetic challenges may pave the way for the design of therapeutic approaches that interfere with the ability of the pathogen to successfully adapt when it invades different niches within its host.

Porphyrin-Based Hole-Transporting Materials for Perovskite Solar Cells: Boosting Performance with Smart Synthesis.

Perovskite solar cells (PSCs) are becoming a promising and revolutionary advancement within the photovoltaic field globally. Continuous improvement in efficiency, straightforward processing methods, and use of lightweight and cost-effective materials represent superior features, among other notable aspects. Still, long-term stability and durability are issues to address to facilitate widespread commercial adoption and practical application prospects. Research has focused on overcoming these challenges, and charge transport materials play a critical role in determining charge dynamics, photovoltaic performance, and device stability. Conventional hole-transporting materials (HTMs), spiro-OMeTAD and PTAA, contribute to remarkable power conversion efficiencies owing to high thin-film quality and matched energy alignment. However, they often show a high material cost, low carrier mobility, and poor stability, which greatly limit their practical applications. Now, this review outlines recent advances in synthetic approaches to porphyrin-based HTMs to tune the charge dynamics by optimizing their molecular structures and properties. The main structural features comprise porphyrins of A4-type, trans A2B2-type, and photosynthetic pigment analogues. Strategies include well-established routes to provide the required macrocycles, such as condensation of pyrrole or dipyrromethanes with suitable aldehydes, metalation of the porphyrin inner core, and postfunctionalization of peripheral positions. These functionalizations involve conventional procedures (e.g., halogenation, esterification, transesterification, nucleophilic oxidation, reduction, and nucleophilic substitution) as well as metal-catalyzed ones such as Suzuki-Miyaura, Sonogashira, Buchwald-Hartwig, and Ullmann cross-coupling reactions. As HTMs can also protect the perovskite layer from the external environment, porphyrin structures play a pivotal role in chemical, mechanical, and environmental stability, with their high hydrophobicity ability as the most significant parameter. The impact of porphyrins on the hole hopping of other HTMs while acting as an additive or an interlayer, passivating defects, and improving charge transport is also highlighted to provide real insights into ways to develop efficient and stable porphyrin-based materials for PSCs. This perspective aims to guide the scientific community in the design of new porphyrin molecules to place PSCs as an outperformer in photovoltaic technologies.

Prognostic Implications and Alterations in Left Atrial Deformation Following Transcatheter Aortic Valve Implantation.

AIMS: To evaluate the prognostic implications of left atrial reservoir strain-defined diastolic dysfunction (LARS-DD) grade in patients undergoing TAVI for severe aortic stenosis (AS) and to determine if post-TAVI LARS was more closely associated with new-onset atrial fibrillation than pre-TAVI LARS. METHODS AND RESULTS: Pre-TAVI LARS-DD was evaluated by speckle-tracking echocardiography and was assigned as grade 0 to 1 (LARS≥24%), grade 2 (LARS≥19 to <24%) and grade 3 (LARS<19%). Patients were followed-up for the primary endpoint of all-cause mortality from the date of TAVI. For the secondary endpoint, patients with pre- and post-TAVI LARS measurements and no history of atrial fibrillation were evaluated for the occurrence of new-onset atrial fibrillation. A total of 601 patients (median age 81 [76-85] years, 53% male) were included. Overall, 169 patients (28%) were LARS-DD grade 0/1, 96 patients (16%) were LARS-DD grade 2 and 336 (56%) were LARS-DD grade 3. Over a median follow-up of 40 (IQR 26-58) months, a total of 258 (43%) patients died. In a comprehensive multivariable Cox regression model, LARS-DD grade was independently associated with all-cause mortality (adjusted HR 1.28 per one-grade increase, 95%CI 1.07-1.53, P=0.007). For the secondary endpoint of new-onset atrial fibrillation, a total of 285 patients were evaluated. Post-TAVI LARS (SDHR 1.14 per 1%<20%, 95%CI 1.05-1.23, P=0.0009), but not pre-TAVI LARS (P=0.93) was independently associated with new-onset atrial fibrillation. CONCLUSIONS: Increasing LARS-DD grade was independently associated with long-term post-TAVI survival in patients with severe AS. Post-TAVI LARS was closely related to the occurrence of new-onset atrial fibrillation.