A nuclear architecture screen in Drosophila identifies Stonewall as a link between chromatin position at the nuclear periphery and germline stem cell fate.

The association of genomic loci to the nuclear periphery is proposed to facilitate cell type-specific gene repression and influence cell fate decisions. However, the interplay between gene position and expression remains incompletely understood, in part because the proteins that position genomic loci at the nuclear periphery remain unidentified. Here, we used an Oligopaint-based HiDRO screen targeting ∼1000 genes to discover novel regulators of nuclear architecture in Drosophila cells. We identified the heterochromatin-associated protein Stonewall (Stwl) as a factor promoting perinuclear chromatin positioning. In female germline stem cells (GSCs), Stwl binds and positions chromatin loci, including GSC differentiation genes, at the nuclear periphery. Strikingly, Stwl-dependent perinuclear positioning is associated with transcriptional repression, highlighting a likely mechanism for Stwl's known role in GSC maintenance and ovary homeostasis. Thus, our study identifies perinuclear anchors in Drosophila and demonstrates the importance of gene repression at the nuclear periphery for cell fate.

Genome organization regulates nuclear pore complex formation and promotes differentiation during Drosophila oogenesis.

Genome organization can regulate gene expression and promote cell fate transitions. The differentiation of germline stem cells (GSCs) to oocytes in Drosophila involves changes in genome organization mediated by heterochromatin and the nuclear pore complex (NPC). Heterochromatin represses germ cell genes during differentiation, and NPCs anchor these silenced genes to the nuclear periphery, maintaining silencing to allow for oocyte development. Surprisingly, we found that genome organization also contributes to NPC formation, mediated by the transcription factor Stonewall (Stwl). As GSCs differentiate, Stwl accumulates at boundaries between silenced and active gene compartments. Stwl at these boundaries plays a pivotal role in transitioning germ cell genes into a silenced state and activating a group of oocyte genes and nucleoporins (Nups). The upregulation of these Nups during differentiation is crucial for NPC formation and further genome organization. Thus, cross-talk between genome architecture and NPCs is essential for successful cell fate transitions.

Investigating intervention components and their effectiveness in promoting environmentally sustainable diets: a systematic review.

Global food systems contribute 30% of global greenhouse gas emissions, threatening the global temperature targets of the Paris Agreement. Diets in high-income countries exceed the recommendations for animal-based foods, whereas consumption of fruits and vegetables is below recommendations. Shifting to a more plant-based diet can reduce up to 30% of greenhouse gas emissions from diet and also reduce risk of chronic disease. Interventions addressing sustainable dietary behaviour, defined by a shift in dietary patterns and food-waste practices, could therefore improve population and planetary health, but knowledge of the interventions that are likely to be most effective in changing sustainable dietary behaviour is so far limited. This systematic review aimed to investigate, classify, and assess the effectiveness of interventions that promote environmentally sustainable diets in high-income countries. We searched MEDLINE, Embase, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature for randomised controlled trials and quasi-experimental trials published from inception until June 16, 2022, evaluating the effectiveness of any intervention promoting environmentally sustainable dietary behaviour. Studies were eligible for inclusion if they included adults and children from high-income countries (as defined by the World Bank classification) and used individual-level behaviour change interventions. Online choice experiments and studies reporting results on only change in fruit and vegetable consumption were excluded. Interventions were classified using the nine intervention functions of the behaviour change wheel. Data were extracted on number of participants, intervention characteristics, diet change (eg, meat consumption and fruit and vegetable intake), food waste, greenhouse gas emissions, and health outcomes. 13 studies were identified and included in the systematic review. Articles were from six different countries (ie, Canada, the USA, Germany, the UK, the Netherlands, Italy). Six of the nine intervention functions of the behaviour change wheel were used. Interventions using education had the most robust evidence base, whereas interventions using persuasion had the strongest effect on reducing meat consumption. Overall, interventions using education in combination with other factors were most successful. Five studies had high risk of bias, five had some concerns of bias, and three had low risk of bias. This systematic review provides insight into the effectiveness of behavioural interventions to meet health and climate change goals through promotion of environmentally sustainable diets. Evidence supports the use of multicomponent interventions through education, persuasion, and environmental restructuring to provide opportunity for change. Little high-quality research was available, and more robustly designed intervention studies are needed to inform future guidelines and policies.

Optimization of an anatomically and electrically detailed rodent subthalamic nucleus neuron model.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for Parkinson's disease, but its mechanisms of action remain unclear. Detailed multi-compartment computational models of STN neurons are often used to study how DBS electric fields modulate the neurons. However, currently available STN neuron models have some limitations in their biophysical realism. In turn, the goal of this study was to update a detailed rodent STN neuron model originally developed by Gillies & Willshaw [2006]. Our design requirements consisted of explicitly representing an axon connected to the neuron and updating the ion channel distributions based on the experimental literature to match established electrophysiological features of rodent STN neurons. We found that adding an axon to the STN neuron model substantially altered its firing characteristics. We then used a genetic algorithm to optimize the biophysical parameters of the model. The optimized model exhibited spontaneous firing, action potential shape, hyperpolarization response, and frequency-current curve that aligned well with experimental recordings from STN neurons. Subsequently, we evaluated the general compatibility of the updated biophysics by applying them to 26 different STN neuron morphologies derived from 3D anatomical reconstructions. The different morphologies affected the firing behavior of the model, but the updated biophysics were robustly capable of maintaining the desired electrophysiological features. The new STN neuron model developed in this work offers a valuable tool for studying STN neuron firing properties, and may find application in simulating STN local field potentials or analysis of the effects of STN DBS.

The Impact of Parental Involvement in the Prevention and Management of Obesity in Children: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Obesity in children is a critical public health issue in developed countries and developing countries. The establishment of health-related behaviors in childhood, significantly influenced by parental involvement, underscores the need for effective intervention measures. AIM: This original research is a systematic review and meta-analysis that aimed to investigate the impact of parental involvement on the prevention and management of childhood obesity, focusing on outcomes such as BMI z-score, exercise levels, screen time, dietary self-efficacy, and percentage body fat. METHODS: Adhering to the PRISMA guidelines, we conducted a systematic review and meta-analysis of 12 randomized controlled trials (RCTs) identified through comprehensive searches of PubMed, Scopus, Web of Science, and the Cochrane Library, including RCTs involving children aged 2-18 years with parental or caregiver participation, reporting on the specified outcomes. Data analysis was performed using RevMan 5.3, employing a random effects model. RESULTS: A total of 5573 participants were included. The meta-analysis revealed a significant reduction in BMI z-score (MD = -0.06, 95% CI: -0.09 to -0.02, p = 0.005, I2 = 58%), a non-significant increase in exercise levels (SMD = 0.26, 95% CI: -0.01 to 0.52, p = 0.05, I2 = 52%), and a significant reduction in screen time (MD = -0.36 h per day, 95% CI: -0.61 to -0.11, p = 0.005, I2 = 0%). Dietary self-efficacy also improved significantly (MD = 0.59, 95% CI: 0.12 to 1.05, p = 0.01, I2 = 0%). However, changes in percentage body fat did not reach statistical significance (MD = -1.19%, 95% CI: -2.8% to 0.41%, p = 0.15, I2 = 0%). CONCLUSION: Parental involvement in childhood obesity interventions significantly impacts BMI z-score, exercise levels, screen time, and dietary self-efficacy but not percentage body fat. These findings highlight the importance of engaging parents in obesity prevention and management strategies.

Uveitis Profile in Children and Its Impact on Vision at Queen Rania Children's Hospital.

AIM: The aim of this study was to explore the patterns of pediatric uveitis and the types of ocular complications of uveitis and to determine the possible risk factors associated with visual impairment. METHOD: This was a cross-sectional study conducted at Queen Rania Children's Hospital between June 2020 and June 2023. All children diagnosed with uveitis were enrolled in the study. After collecting data from the patients and reviewing their medical records regarding age, gender, and past ocular and medical history, the patients were subjected to a detailed ophthalmic exam including best-corrected visual acuity (BCVA). Anterior segment exam using the slit lamp, intraocular pressure exam using Goldmann applanation tonometry, and posterior segment exam using 78 and 90 diopter Volk lenses were performed. Patients with other ocular diseases that affected visions not related to uveitis were excluded from the study. RESULTS: A total of 82 children, accounting for 130 eyes, were enrolled in this study, with ages ranging from 2 to 16 years (mean age 10.5±4.3 years). Among them, 27 were males, constituting 32.9% of the participants. Unilateral uveitis was observed in 34 eyes, representing 26.2% of cases. The mean age of uveitis onset was 6.9±1.9 years, and the mean disease duration was 4.8±0.4 years. The majority of cases i.e. 90.8% (n = 74) were non-infectious, with 92.3% (n = 76) classified as non-granulomatous and 79.2% (n = 65) categorized as chronic. Anterior uveitis was the most prevalent site of inflammation in 70.8% of cases (n = 58), followed by panuveitis in 20.0% of cases (n = 16), intermediate uveitis in 6.2% of cases (n = 5), and posterior uveitis in 3.0% of cases (n = 2). The cause of uveitis could not be identified in 40.0% (n = 33) of cases. Juvenile idiopathic uveitis emerged as the most commonly known disorder associated with uveitis in 40.0% (n = 33) of cases. Complications were identified in 52.3% (n = 43) of cases, with posterior synechiae being the most prevalent; 26.9% (n = 22) demonstrated an improvement in BCVA, while 21.5% (n = 18) experienced a decline in BCVA relative to the initial assessment Conclusion: Pediatric uveitis tends to manifest as anterior, chronic, bilateral, and non-granulomatous. Higher frequencies of severe visual impairment are linked to panuveitis, infectious and granulomatous uveitis, early-onset, long-duration cases, and male gender. The use of biologics has a positive effect, significantly improving or preserving visual acuity.

Knowledge, Attitude, Motivators, and Barriers to Blood Donation Among Adults in Al-Qunfudah Governorate, Saudi Arabia: A Cross-Sectional Study.

BACKGROUND: Blood transfusion is one of the most important aspects of managing patients with a variety of medical disorders like thalassemia and sickle cell anemia. Despite this fact, many Saudis hesitate to donate blood and do not know whether blood banks need blood. OBJECTIVES: To evaluate the knowledge, attitude, motivators, and barriers to blood donation among adults in Al-Qunfudah governorate, Saudi Arabia. METHODS: A descriptive cross-sectional study was performed on a convenience sample of 416 adults living in Al-Qunfudah governorate and its dependence, using an online self-administered questionnaire. The obtained data were analyzed statistically using SPSS version 21 (IBM Corp., Armonk, New York, USA). RESULTS: Among 416 respondents, exactly 232 (55.8%) had overall good knowledge regarding blood donation, and 334 (80.3%) positively perceived it. The best knowledge about blood donation was detected among those aged 21-24 years (p = 0.012), males (p = 0.008), university-educated (p = 0.048), having a government job (p = 0.001), and having a history of donating blood (p = 0.001). The motivators included religious motives (88.2%, n = 367), feelings of self-satisfaction (63.2%, n = 263), and restoring blood circulation (56.7%, n = 236). Barriers to blood donation were fear of being infected (27.6%, n = 115), needle phobia (23.6%, n = 98), fear of general weakness (22.8%, n = 95), didn't know how to donate (16.8%, n = 70), and fear of seeing blood (13.2%, n = 55). CONCLUSION: Although adults in the Al-Qunfudah governorate of Saudi Arabia had positive attitudes toward blood donation, they possessed inadequate knowledge about it. Being younger, male, university-educated, having government jobs, and having a past history of donating blood were factors associated with good knowledge of blood donation. The most common motivators were religious, financial, and maintaining health. However, fear of infection, needle sticks, fear of pain, and hemophobia were the recorded barriers. Public health education is recommended to tackle public concerns regarding blood donation and present its benefits.

The genetic basis of early-onset hereditary ataxia in Iran: results of a national registry of a heterogeneous population.

BACKGROUND: To investigate the genetics of early-onset progressive cerebellar ataxia in Iran, we conducted a study at the Children's Medical Center (CMC), the primary referral center for pediatric disorders in the country, over a three-year period from 2019 to 2022. In this report, we provide the initial findings from the national registry. METHODS: We selected all early-onset patients with an autosomal recessive mode of inheritance to assess their phenotype, paraclinical tests, and genotypes. The clinical data encompassed clinical features, the Scale for the Assessment and Rating of Ataxia (SARA) scores, Magnetic Resonance Imaging (MRI) results, Electrodiagnostic exams (EDX), and biomarker features. Our genetic investigations included single-gene testing, Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS). RESULTS: Our study enrolled 162 patients from various geographic regions of our country. Among our subpopulations, we identified known and novel pathogenic variants in 42 genes in 97 families. The overall genetic diagnostic rate was 59.9%. Notably, we observed PLA2G6, ATM, SACS, and SCA variants in 19, 14, 12, and 10 families, respectively. Remarkably, more than 59% of the cases were attributed to pathogenic variants in these genes. CONCLUSIONS: Iran, being at the crossroad of the Middle East, exhibits a highly diverse genetic etiology for autosomal recessive hereditary ataxia. In light of this heterogeneity, the development of preventive strategies and targeted molecular therapeutics becomes crucial. A national guideline for the diagnosis and management of patients with these conditions could significantly aid in advancing healthcare approaches and improving patient outcomes.

Optimization of Culture Conditions and Batch Process Control for the Augmented Production of Bacteriocin by Bacillus Species.

The emergence of antibiotic-resistant microorganisms poses a significant threat to human health worldwide. Recent advances have led to the discovery of molecules with potent antimicrobial activity from environmental sources. In this study, fifteen bacterial isolates were obtained from agricultural and polluted soil samples collected from different areas of the cities of Jizan and Jeddah. These isolates were screened for antagonistic activity against a set of human pathogenic bacterial strains. The results showed that two Bacillus strains, identified as Bacillus atrophaeus and Bacillus amyloliquefaciens based on 16S rDNA, synthesized bacteriocin with strong antibacterial activity against Methicillin-resistant Staphylococcus aureus (MRSA) ATCC 33591, Pseudomonas aeruginosa ATCC 9027, Salmonella typhimum ATCC 14028, carbapenem-resistant E. coli, and MRSA 2. To optimize bacteriocin production, the effects of medium composition, incubation period, temperature, and pH were investigated. Nutrient broth and Mueller-Hinton broth were chosen as the optimal original media for bacteriocin production. The optimal incubation period, temperature, and pH were found to be 48 h at 37 °C and 7 pH in Bacillus atrophaeus and 72 h at 37 °C and 8 pH in Bacillus amyloliquefaciens. Batch cultures of Bacillus atrophaeus and Bacillus amyloliquefaciens were grown in a 10 L benchtop bioreactor, and pH control was found to significantly increase the production of bacteriocin by two-fold compared to uncontrolled conditions. The time course of growth, substrate consumption, pH, and enzyme production were investigated. This study demonstrates the potential of optimizing culture conditions and batch process control to enhance bacteriocin production by Bacillus spp.

Dissecting deep brain stimulation evoked neural activity in the basal ganglia.

Deep brain stimulation (DBS) is an established therapeutic tool for the treatment of Parkinson's disease (PD). The mechanisms of DBS for PD are likely rooted in modulation of the subthalamo-pallidal network. However, it can be difficult to electrophysiologically interrogate that network in human patients. The recent identification of large amplitude evoked potential (EP) oscillations from DBS in the subthalamic nucleus (STN) or globus pallidus internus (GPi) are providing new scientific opportunities to expand understanding of human basal ganglia network activity. In turn, the goal of this review is to provide a summary of DBS-induced EPs in the basal ganglia and attempt to explain various components of the EP waveforms from their likely network origins. Our analyses suggest that DBS-induced antidromic activation of globus pallidus externus (GPe) is a key driver of these oscillatory EPs, independent of stimulation location (i.e. STN or GPi). This suggests a potentially more important role for GPe in the mechanisms of DBS for PD than typically assumed. And from a practical perspective, DBS EPs are poised to become clinically useful electrophysiological biomarker signals for verification of DBS target engagement.

Subcallosal cingulate deep brain stimulation evokes two distinct cortical responses via differential white matter activation.

Subcallosal cingulate (SCC) deep brain stimulation (DBS) is an emerging therapy for refractory depression. Good clinical outcomes are associated with the activation of white matter adjacent to the SCC. This activation produces a signature cortical evoked potential (EP), but it is unclear which of the many pathways in the vicinity of SCC is responsible for driving this response. Individualized biophysical models were built to achieve selective engagement of two target bundles: either the forceps minor (FM) or cingulum bundle (CB). Unilateral 2 Hz stimulation was performed in seven patients with treatment-resistant depression who responded to SCC DBS, and EPs were recorded using 256-sensor scalp electroencephalography. Two distinct EPs were observed: a 120 ms symmetric response spanning both hemispheres and a 60 ms asymmetrical EP. Activation of FM correlated with the symmetrical EPs, while activation of CB was correlated with the asymmetrical EPs. These results support prior model predictions that these two pathways are predominantly activated by clinical SCC DBS and provide first evidence of a link between cortical EPs and selective fiber bundle activation.

Comparing the effects of various ß-blockers on cardiovascular mortality in breast cancer patients.

BACKGROUND: Cardiovascular (CV) disease is a leading cause of death in breast cancer (BC) patients due to the increased age and treatments. While individual ß-blockers have been investigated to manage CV complications, various ß-blockers have not been compared for their effects on CV death in this population. We aimed to compare CV mortality in older BC patients taking one of the commonly used ß-blockers. METHODS: This retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results (SEER) - Medicare data (2010-2015). Patients of age 66 years or older at BC diagnosis receiving metoprolol, atenolol, or carvedilol monotherapy were included. The competing risk regression model was used to determine the risk of CV mortality in the three ß-blocker groups. The multivariable model was adjusted for demographic and clinical covariates. The adjusted hazard ratio (HR) and 95% confidence intervals (CI) were reported for the risk of CV mortality. RESULTS: The study cohort included 6,540 patients of which 55% were metoprolol users, 30% were atenolol users, and 15% were carvedilol users. Metoprolol was associated with a 37% reduced risk of CV mortality (P = 0.03) compared to carvedilol after adjusting for the covariates (HR = 0.63; 95% CI 0.41-0.96). No significant difference in the risk of CV mortality between atenolol and carvedilol users was observed (HR = 0.74; 95% CI 0.44-1.22). CONCLUSIONS: Our findings suggest that metoprolol is associated with a reduced risk of CV mortality in BC patients. Future studies are needed to confirm these findings and understand the mechanism of action.

Frequency and characteristics of chronic fatigue syndrome in multiple sclerosis patients at a university hospital in Eastern Saudi Arabia.

BACKGROUND: Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease that affects various parts of the central nervous system. Fatigue, a common symptom, transient, prolonged, or chronic experienced by individuals with MS, can significantly impact daily functioning. It can be associated with underlying pathological processes or can have an idiopathic cause, such as chronic fatigue syndrome (CFS). The study aimed to assess the presence and etiology of fatigue in MS patients and its relationship with CFS. MATERIALS AND METHODS: This cross-sectional study was conducted in the Eastern Province of Saudi Arabia. Data were collected using a questionnaire from a sample of 225 MS patients receiving care at our university hospital. The questionnaire included the Centers for Disease Control and Prevention (CDC) criteria for diagnosing CFS and the Expanded Disability Status Scale to evaluate fatigue in MS patients. RESULTS: Of the total of 225 MS patients who participated in this study, 87.1% were diagnosed with relapsing-remitting MS, 6.7% with primary progressive MS, 3.6% with clinically isolated syndrome, and 2.7% with secondary progressive MS. About 53% had experienced fatigue that persisted for over 6 months. Analysis of CFS diagnosis revealed that 7.3% of patients met both CDC criteria and self-reported answers while 17.5% reported having CFS despite not meeting the CDC criteria. These findings highlight a significant lack of agreement between patient-reported diagnoses and established criteria, indicating poor agreement (P = 0.028). CONCLUSION: The study found an association between CFS and MS, and a significant impact on daily functioning. The study revealed lack of agreement between patient-reported diagnoses and established criteria for CFS. This emphasizes the need for a standardized approach to diagnosis and evaluation of fatigue in MS patients.

Adverse Events of the Long-Term Use of Opioids for Chronic Non-cancer Pain: A Narrative Review.

BACKGROUND: The long-term use of opioids for chronic non-cancer pain (CNCP) has drawn more attention and debate. Although opioids are frequently used to treat chronic pain, their effectiveness and safety over extended periods are still unknown. OBJECTIVES: The purpose of this review is to provide an overview of what is currently known about the adverse events of long-term use of opioids in CNCP. It also delivers patient-centered strategies designed to mitigate these risks. METHODS: We conducted a literature search in PubMed, MEDLINE, EMBASE, and Web of Science databases. Search terms included CNCP, pain pathophysiology, opioid pharmacodynamics, opioid prescribing trends, guidelines for opioid use, and opioid side effects.  Results: Our review highlights that while opioids may provide short-term relief from CNCP, their effectiveness diminishes over time due to the development of opioid tolerance. This tolerance often leads to increased dosages, which can subsequently result in opioid dependence. Additionally, long-term opioid therapy is associated with a spectrum of adverse effects, including constipation, drowsiness, respiratory depression, and potential for drug interactions. Furthermore, our review indicates that alternative pain management strategies play a crucial role in controlling CNCP. They offer significant benefits with fewer adverse events. These strategies include non-opioid medications, physical therapy, cognitive-behavioral therapy (CBT), various interventional procedures, injection therapy, and acupuncture. CONCLUSION: Using opioids to manage CNCP presents several challenges. Given these challenges, alternative treatments are being considered as viable options. Moreover, it is crucial to customize treatment plans to align with the patients' specific health requirements, existing conditions, and potential risks to ensure the best possible outcomes.

Concomitant Lymphocytic Colitis With Recurrent Clostridium difficile Infection.

Microscopic colitis is a clinicopathological diagnosis that is characterized by chronic microscopic inflammation of the colon and presents with chronic watery diarrhea. There are following two subtypes of microscopic colitis: lymphocytic colitis and collagenous colitis. This is a case of a 70-year-old female with a history of Clostridium difficile infections who presented with persistent watery diarrhea and was diagnosed with lymphocytic colitis in the setting of a concomitant C. difficile infection. Given her clinical presentation, the patient was initiated on empiric treatment for C. difficile infection and showed a lack of clinical improvement with persistent watery diarrhea and elevated white blood cell count. The patient's symptoms resolved upon the confirmatory diagnosis and treatment of lymphocytic colitis. This study illustrates the importance of assessing for, diagnosing, and treating lymphocytic colitis in patients with chronic non-resolving watery diarrhea, especially in the setting of concomitant or recurrent C. difficile infections. Additionally, it emphasizes the need for further characterization of the relationship between C. difficile infection and microscopic colitis.

Addressing nutritional issues and eating behaviours among university students: a narrative review.

University life is a critical period for establishing healthy eating habits and attitudes. However, university students are at risk of developing poor eating habits due to various factors, including economic conditions, academic stress and lack of information about nutritional concepts. Poor diet quality leads to malnutrition or overnutrition, increasing the risk of preventable diseases. Food environments on university campuses also play a significant role in shaping the dietary habits of students, with the availability of and accessibility to healthy food options being important factors influencing food choices and overall diet quality. Disordered eating habits and body dissatisfaction are prevalent among university students and can lead to eating disorders. Income and living arrangements also influence dietary habits, with low household income and living alone being associated with unhealthy eating habits. This study is a narrative review that aimed to address nutritional issues and eating behaviours, specifically among university students. We investigated the eating behaviours of university students, including their dietary patterns, food choices and food environments. The objective of this review was to provide insights into the nutritional issues and eating behaviours of university students, with the aim of identifying target areas for intervention to improve the overall health and wellbeing among college students. University food environments need to be restructured to promote healthy eating, including the availability, accessibility, affordability and labelling of healthy foods, and policies to limit the availability of unhealthy foods and drinks on campus.

Synergistic Antibacterial Effect of ZnO Nanoparticles and Antibiotics against Multidrug-Resistant Biofilm Bacteria.

BACKGROUND: The misuse of antibiotics leads to a global increase in antibiotic resistance. Therefore, it is imperative to search for alternative compounds to conventional antibiotics. ZnO nanoparticles (Zn NP) are one of these alternatives because they are an effective option to overcome biofilm bacterial cells and a novel way to overcome multidrug resistance in bacteria. The current research study aims to characterize the efficacy of ZnO nanoparticles alone and in combination with other antibacterial drugs against bacterial biofilms. METHODS: ZnO NPs were prepared by co-precipitation method, and their anti-biofilm and antibacterial activities alone or combined with four types of broad-spectrum antibacterial (Norfloxacin, Colistin, Doxycycline, and Ampicillin) were evaluated against E. coli and S. aureus bacterial strains. Finally, the cytotoxicity and the hemolytic activity were evaluated. RESULTS: ZnO NPs were prepared, and results showed that their size was around 10 nm with a spherical shape and a zeta potential of -21.9. In addition, ZnO NPs were found to have a strong antibacterial effect against Gram-positive and Gram-negative microorganisms, with a minimum inhibitory concentration (MIC) of 62.5 and 125 µg/mL, respectively. Additionally, they could eradicate biofilmforming microorganisms at a concentration of 125 µg/m. ZnO NPs were found to be non-toxic to erythrocyte cells. Still, some toxicity was observed for Vero cells at effective concentration ranges needed to inhibit bacterial growth and eradicate biofilm-forming organisms. When combined with different antibacterial, ZnO NP demonstrated synergistic and additive effects with colistin, and the MIC and MBEC of the combination decreased significantly to 0.976 µg/mL against planktonic and biofilm strains of MDR Gram-positive bacteria, resulting in significantly reduced toxicity. CONCLUSION: The findings of this study encourage the development of alternative therapies with high efficacy and low toxicity. ZnO nanoparticles have demonstrated promising results in overcoming multi-drug resistant bacteria and biofilms, and their combination with colistin has shown a significant reduction in toxicity. Further studies are needed to investigate the potential of ZnO nanoparticles as a viable alternative to conventional antibiotics.

Molecular basis for the transcriptional regulation of an epoxide-based virulence circuit in Pseudomonas aeruginosa.

The opportunistic pathogen Pseudomonas aeruginosa infects cystic fibrosis (CF) patient airways and produces a virulence factor Cif that is associated with worse outcomes. Cif is an epoxide hydrolase that reduces cell-surface abundance of the cystic fibrosis transmembrane conductance regulator (CFTR) and sabotages pro-resolving signals. Its expression is regulated by a divergently transcribed TetR family transcriptional repressor. CifR represents the first reported epoxide-sensing bacterial transcriptional regulator, but neither its interaction with cognate operator sequences nor the mechanism of activation has been investigated. Using biochemical and structural approaches, we uncovered the molecular mechanisms controlling this complex virulence operon. We present here the first molecular structures of CifR alone and in complex with operator DNA, resolved in a single crystal lattice. Significant conformational changes between these two structures suggest how CifR regulates the expression of the virulence gene cif. Interactions between the N-terminal extension of CifR with the DNA minor groove of the operator play a significant role in the operator recognition of CifR. We also determined that cysteine residue Cys107 is critical for epoxide sensing and DNA release. These results offer new insights into the stereochemical regulation of an epoxide-based virulence circuit in a critically important clinical pathogen.