Biallelic NUDT2 variants defective in mRNA decapping cause a neurodevelopmental disease.

Dysfunctional RNA processing caused by genetic defects in RNA processing enzymes has a profound impact on the nervous system, resulting in neurodevelopmental conditions. We characterized a recessive neurological disorder in 18 children and young adults from 10 independent families typified by intellectual disability, motor developmental delay and gait disturbance. In some patients peripheral neuropathy, corpus callosum abnormalities and progressive basal ganglia deposits were present. The disorder is associated with rare variants in NUDT2, a mRNA decapping and Ap4A hydrolysing enzyme, including novel missense and in-frame deletion variants. We show that these NUDT2 variants lead to a marked loss of enzymatic activity, strongly implicating loss of NUDT2 function as the cause of the disorder. NUDT2-deficient patient fibroblasts exhibit a markedly altered transcriptome, accompanied by changes in mRNA half-life and stability. Amongst the most up-regulated mRNAs in NUDT2-deficient cells, we identified host response and interferon-responsive genes. Importantly, add-back experiments using an Ap4A hydrolase defective in mRNA decapping highlighted loss of NUDT2 decapping as the activity implicated in altered mRNA homeostasis. Our results confirm that reduction or loss of NUDT2 hydrolase activity is associated with a neurological disease, highlighting the importance of a physiologically balanced mRNA processing machinery for neuronal development and homeostasis.

Unloading the Left Ventricle in Venoarterial ECMO: In Whom, When, and How?

Venoarterial extracorporeal membrane oxygenation provides cardiorespiratory support to patients in cardiogenic shock. This comes at the cost of increased left ventricle (LV) afterload that can be partly ascribed to retrograde aortic flow, causing LV distension, and leads to complications including cardiac thrombi, arrhythmias, and pulmonary edema. LV unloading can be achieved by using an additional circulatory support device to mitigate the adverse effects of mechanical overload that may increase the likelihood of myocardial recovery. Observational data suggest that these strategies may improve outcomes, but in whom, when, and how LV unloading should be employed is unclear; all techniques require balancing presumed benefits against known risks of device-related complications. This review summarizes the current evidence related to LV unloading with venoarterial extracorporeal membrane oxygenation.

14-Electron Redox Chemistry Enabled by Salen-Based π-Conjugated Framework Polymer Boosting High-Performance Lithium-Ion Storage.

A paucity of redox centers, poor charge transport properties, and low structural stability of organic materials obstruct their use in practical applications. Herein, these issues have been addressed through the use of a redox-active salen-based framework polymer (RSFP) containing multiple redox-active centers in π-conjugated configuration for applications in lithium-ion batteries (LIBs). Based on its unique architecture, RSFP exhibits a superior reversible capacity of 671.8 mAh g-1 at 0.05 A g-1 after 168 charge-discharge cycles. Importantly, the lithiation/de-lithiation performance is enhanced during operation, leading to an unprecedented reversible capacity of 946.2 mAh g-1 after 3500 cycles at 2 A g-1. The structural evolution of RSFP is studied ex situ using X-ray photoelectron spectroscopy, revealing multiple active C═N, C─O, and C═O sites and aromatic sites such as benzene rings. Remarkably, the emergence of C═O originated from C─O is triggered by an electrochemical process, which is beneficial for improving reversible lithiation/delithiation behavior. Furthermore, the respective strong and weak binding interactions between redox centers and lithium ions, corresponding to theoretical capacities of 670.1 and 938.2 mAh g-1, have been identified by density functional theory calculations manifesting 14-electron redox reactions. This work sheds new light on routes for the development of redox-active organic materials for energy storage applications.

Enhanced Photo/Electrocatalytic Hydrogen Evolution by Hydrothermally Derived Cu-Doped TiO2 Solid Solution Nanostructures.

Highly efficient nanocatalysts with a high specific surface area were successfully synthesized by a cost-effective and environmentally friendly hydrothermal method. Structural and elemental purity, size, morphology, specific surface area, and band gap of pristine and 1 to 5% Cu-doped TiO2 nanoparticles were characterized by powder X-ray diffraction (PXRD), X-ray photoelectron spectroscopy (XPS), electron paramagnetic resonance (EPR), energy dispersive X-ray analysis (EDAX), inductively coupled plasma mass spectrometry (ICP-MS), liquid chromatography-high resolution mass spectrometry (LC-HRMS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), BET surface area, Raman spectroscopy, photoluminescence spectroscopy (PL) and UV-visible diffused reflectance spectroscopy (UV-DRS) studies. The XPS and EPR findings indicated the successful integration of Cu ions into the TiO2 lattice. UV-DRS and BET surface area investigations revealed that with an increase in dopant concentration, Cu-doped TiO2 NPs show a decrease in band gap (3.19-3.08 eV) and an increase in specific surface area (169.9-188.2 m2/g). Among all compositions, 2.5% Cu-doped TiO2 has shown significant H2 evolution with an apparent quantum yield of 17.67%. Furthermore, the electrochemical water-splitting study shows that 5% Cu-doped TiO2 NPs have superiority over pristine TiO2 for H2 evolution reaction. It was thus revealed that the band gap tuning with the desired dopant concentration led to enhanced photo/electrocatalytic sustainable energy applications.

Ceria nanocatalyst-supported oxidative organic transformations of aromatic alcohols andp-nitrotoluene.

Hydrothermally derived nanocubes of CeO2(10 nm) were explored as an efficient heterogeneous catalyst in the partial oxidation of aromatic alcohols to the corresponding aldehydes and aerobic oxidation ofp-nitrotoluene top-nitrobenzoic acid. The CeO2nanocatalyst was characterized by x-ray diffraction, transmission electron microscopy (TEM), energy dispersive spectroscopy, x-ray photoelectron spectroscopy, Brunauer-Emmett-Teller (BET) surface area analysis, Fourier transform infrared spectroscopy, thermal gravimetric analysis and ultraviolet-visible spectroscopy. TEM/high-resolution TEM micrographs reveal a morphology of mostly cubic nanostructures with exposed highly active {100} and {110} facets. The surface area of nanoceria was determined by BET analysis and found to be 33.8 m2g-1. To demonstrate the universality of the catalytic system, the selective oxidation of different substrates of benzylic alcohol and complete oxidation ofp-nitrotoluene was investigated under mild conditions. Absolute selectivity towards their respective aldehydes was found to be 99.50% (benzaldehyde), 90.18% (p-chlorobenzaldehyde), 99.71% (p-nitrobenzaldehyde), 98.10% (p-fluorobenzaldehyde), 94.66% (p-anisaldehyde) and 86.14% (cinnamaldehyde). Moreover, the catalytic oxidative transformation of nitrotoluene results in 100% conversion with 99.29% selectivity towards nitrobenzoic acid.

Photo/electro catalytic green hydrogen production promoted by Ga modified Co0.6Cu0.4Fe2O4 nano catalysts.

The current work concentrates on the fabrication of Ga doped Co0.6Cu0.4Fe2O4 nanocatalysts via sol-gel auto-combustion (SGA) for the production of green and sustainable source of energy i.e., hydrogen through photocatalytic and electrocatalytic routes. Single-phased cubic crystal structure with Fd3m geometry was observed through XRD patterns. FESEM images show the aggregated and spherical shaped grains with distinct grain boundaries and average grain size of 1.04 and 1.39 µm for the Co0.6Cu0.4Fe2O4, and Co0.6Cu0.4Ga0.02Fe1.98O4 nanomaterials. Soft magnetic behaviour with a coercivity (Hc) and saturation magnetization (Ms) of 235.32-357.26 Oe and 54.65-61.11 emu/g was obtained for the produced nanomaterials. The estimation of photocatalytic nature for generating H2 was conducted using the sacrificial agents i.e., 0.128 M Na2S and 0.079 M Na2SO3. The analysis focused on measuring the maximum H2 generation was achieved by photocatalysts throughout three consecutive 4-h cycles. Out of all compositions, Co0.6Cu0.4Ga0.02Fe1.98O4 nanomaterial have the highest photocatalytic activity of 16.71 mmol gcat-1. However, the electrocatalytic behaviour of prepared Co0.6Cu0.4GaxFe2-xO4 (x = 0.00-0.03) electrocatalysts were determined for HER (Hydrogen evolution reaction) reaction. The overpotential values of Co0.6Cu0.4Fe2O4, Co0.6Cu0.4Ga0.01Fe1.99O4, Co0.6Cu0.4Ga0.02Fe1.98O4, and Co0.6Cu0.4Ga0.03Fe1.97O4 catalysts at 10 mA cm-2 were -0.81, -0.85, -1.03, and 1.21 V, correspondingly. Thus, at cathode current density of 10 mA/cm-2, an elevation in overpotential was noted, which indicates that the undoped Co0.6Cu0.4Fe2O4 (x = 0.00) electrocatalyst have remarkable electrocatalytic HER activity. Consequently, owing to photo/electro catalytic water splitting traits, the prepared catalysts are highly efficient for the green hydrogen generation.

Appraising and comparing the role of autogenous periosteal graft as a barrier membrane in the treatment of intrabony defects in chronic periodontitis cases: A systematic review and meta-analysis.

Periodontal regeneration refers to procedures aimed at restitution of lost supporting tissue around the periodontally compromised tooth. Regenerative procedures very often include the use of barrier materials to encourage the growth of key surrounding tissues. The current study aimed to evaluate the effectiveness of autogenous periosteal graft as a barrier membrane for the treatment of intrabony defects in chronic periodontitis patients. A total of four data bases MEDLINE (by PubMed), Cochrane database, EBSCO, and Google Scholar were explored to identify the studies in English up to December 2022. An additional hand search of relevant journals was also done. A team of three independent reviewers screened the retrieved articles using the inclusion criteria. Randomized control trials (RCTs) evaluating the effectiveness of autogenous periosteal grafts in the treatment of intrabony defects in chronic periodontitis cases were included in the study. A total of six relevant articles were recognized for data procurement. A total of 117 patients with 68 sites with an age range between 18 years and 55 years were selected. Outcome variables examined were pocket depth (PD), clinical attachment level (CAL), radiographic bone defect fill (BDF), gingival recession (GR), plaque index (PI), gingival index (GI) and bleeding on probing (BOP). Data were analyzed using Revman 5.3 software. The mean differences and 95% confidence interval were used to illustrate the estimate of effect size. There is an equal effect in both groups for the PI, GI, and BOP reduction. For PD reduction, the result was in the favor of periosteal graft with open flap debridement (OFD) group. For CAL gain, radiographic BDF and GR, results also favored the periosteal graft, but no statistically significant difference was found amongst the groups. Within the limitation of the study, it seems that the autogenous periosteal graft can be used successfully along with OFD to treat intrabony defects in chronic periodontitis patients.

Outcomes of biological therapy in patients with severe asthma with chronic rhinosinusitis in Saudi Arabia: patients with nasal polyps versus those without nasal polyps.

BACKGROUND: This study's purposes were to evaluate the impact of biological therapies on outcomes in patients with severe asthma (SA) and chronic rhinosinusitis (CRS) and to compare these effects among those with NP (CRSwNP) versus those without NP (CRSsNP) in the "real-world" setting in Saudi Arabian patients. METHODS: From March to September 2022, a retrospective observational cohort study was undertaken at the severe asthma clinics of the Armed Forces Hospital-Southern Region (AFHSR) and King Khalid University Hospital, Abha, Saudi Arabia, to delineate the effects of dupilumab therapy. Outcomes were assessed, including clinical outcomes, FEV1, and laboratory findings before and one year after dupilumab. Post-therapy effects were compared between CRSwNP and CRSsNP. RESULTS: Fifty subjects were enrolled, with a mean age of 46.56. There were 27 (54%) females and 23(46%) males. Significant improvements in clinical parameters (frequency of asthma exacerbations and hospitalizations, the use of OCs, anosmia, SNOTT-22, and the ACT), FEV1, and laboratory ones (serum IgE and eosinophilic count) were observed 6 and 12 months after using dupilumab (p < 0.001), respectively. However, after 12 months of dupilumab therapy, there were no significant differences between those with and without NP with regards to clinical (anosmia, ACT, and OCs use), laboratory (eosinophilic count, serum IgE level) parameters, and FEV1%. CONCLUSIONS: Patients with CRS experienced significant improvements in clinical, FEV1, and laboratory outcomes after dupilumab therapy. However, these improvements were not maintained when comparing CRSwNP with CRSsNP. There were no significant differences between those with and without NP regarding ACT and OCs use or laboratory (eosinophilic count, serum IgE level) parameters. Further prospective multicenter studies are warranted.

Investigating colostomy-related morbidity in children following stoma formation and closure in a tertiary hospital, Abha, Saudi Arabia: a retrospective cohort study 2024.

BACKGROUND: Overall, stoma-related morbidity affects a reported 20-38% of pediatric patients. However, determining the true incidence of major stoma-related morbidity is challenging due to limited cohort sizes in existing studies. Thus, the aim of this study was to investigate colostomy related morbidity among children both after stoma formation and stoma closure. METHODOLOGY: This is a retrospective cohort hospital-based study, conducted in an Abha maternity and children hospital, between August 1, 2018, and August 1, 2023, among 126 pediatric patients (aged 0-12 years) who underwent colostomy formation and subsequent closure during the study period. Data were collected from medical records. Data was analyzed using Statistical Package for Social Sciences (SPSS) v.26. RESULTS: This study included a total of 126 children who underwent colostomy. (N = 37, 29.4%) of cases included in this study were emergency cases, while (N = 89, 70.6%) were elective. A variety of antibiotics were used for surgical prophylaxis, metronidazole (77%) and cefuroxime (62.7%) were the most prevalent. Oral feeding was started after 5-6 days in more than one third of cases (39.7%). Wound infection (N = 15, 11.9%) was the most reported post-operative complication, followed with bowel obstruction (N = 6, 4.8%). Emergency cases had a longer duration of hospital stay than elective cases; this difference was statistically significant (P = .04). CONCLUSIONS: Majority of patients reported no stoma related complications, while among those who reported complications, wound infection was the most reported complication, followed by bowel obstruction.

Copper/Tin Nanocomposites-Loaded Exosomes Induce Apoptosis and Cell Cycle Arrest at G0/G1 Phase in Skin Cancer Cell Line.

This study aims to explore the efficacy of Copper/Tin (CuS/SnS) nanocomposites loaded into exosomes against skin cancer A431 cell line. CuS/SnS nanocomposites (S1, S2, S3) were synthesized and characterized, then loaded into exosomes (Exo) (S1-Exo, S2-Exo and S3-Exo) and characterized. After that, the loaded samples were investigated in vitro against A431 using cytotoxicity, apoptosis, and cell cycle assays. CuS/SnS nanocomposites were indexed to hexagonal CuS structure and orthorhombic α-SnS phase and showed nano-rode shape. The exosomes loaded with nanocomposites were regular and rounded within the size of 120 nm, with no signs of broken exosomes or leakage of their contents. The cytotoxicity assay indicated the enhanced cytotoxic of S1-Exo versus the free nano-form S1 on A431. Interestingly, S1-Exo recorded 1.109 times more than DOX in its anti-skin cancer capacity. Moreover, S1-Exo recorded 40.2 % for early apoptosis and 22.1 % for late apoptosis. Furthermore, it displayed impact in arresting the cancer cell cycle at G0/G1 phase and reducing G2/M phase. Noteworthy, loaded nanocomposites were safe against normal HSF skin cells. In conclusion, the loaded CuS/SnS nanocomposites into the exosomes could be of great potential as anti-skin cancer candidates through induction of apoptosis and promotion of the cell cycle arrest at G0/G1 phase.

Assessment of the quality of root canal fillings performed on extracted teeth by undergraduate dental students in a sample from Saudi Arabia.

BACKGROUND: The educational process in the field of endodontics commences with preclinical exercises to enhance students' proficiency in cleaning, shaping, and performing root canal fillings. Therefore, this study aimed to radiographically evaluate the technical quality of root canal fillings performed by preclinical students on extracted teeth at the College of Dentistry, University of Ha'il, Saudi Arabia. METHODS: A total of 788 extracted human teeth received root canal treatment by undergraduate students. The samples were then gathered and radiographically assessed using the three quality criteria of length, density, and taper. The category of root canal fillings was classified as either acceptable or unacceptable. The criteria for evaluating the acceptability of filling quality were defined based on the presence of adequate length, density, and taper. The effectiveness of root canal fillings was also evaluated in relation to the tooth type, sex, and treatment year. The agreement between the examiners was evaluated using Cohen's kappa test, and the relationship between the research variables was determined using the chi-squared test. The significance threshold was set at 0. 05. RESULTS: The overall quality of root filling was determined to be satisfactory in 532 (67.5%) of 788 endodontically treated extracted teeth. The majority of the research sample (88.1%) had enough length, 89.6% had adequate density, and 86.4% had acceptable taper. The quality of anterior teeth was substantially better than that of posterior teeth (p < 0.001). Our findings showed that the quality of root canals was better in 2022 than it had been in earlier years (p = 0.001). The three RCT quality criteria differed significantly when compared between sexes (p = 0.002). CONCLUSIONS: The quality of the root canal fillings completed by undergraduate students was rated as acceptable. The findings of the research suggest that the implementation of routine assessments to evaluate the technical competence of undergraduate dental students performing root canal treatments could provide significant insights into the efficacy of the curriculum requirements.

The impact of study habits and personal factors on the academic achievement performances of medical students.

BACKGROUND: Academic achievement is essential for all students seeking a successful career. Studying habits and routines is crucial in achieving such an ultimate goal. OBJECTIVES: This study investigates the association between study habits, personal factors, and academic achievement, aiming to identify factors that distinguish academically successful medical students. METHODS: A cross-sectional study was conducted at the College of Medicine, King Saud University, Riyadh, Saudi Arabia. The participants consisted of 1st through 5th-year medical students, with a sample size of 336. The research team collected study data using an electronic questionnaire containing three sections: socio-demographic data, personal characteristics, and study habits. RESULTS: The study results indicated a statistically significant association between self-fulfillment as a motivation toward studying and academic achievement (p = 0.04). The results also showed a statistically significant correlation between recalling recently memorized information and academic achievement (p = 0.05). Furthermore, a statistically significant association between preferring the information to be presented in a graphical form rather than a written one and academic achievement was also found (p = 0.03). Students who were satisfied with their academic performance had 1.6 times greater chances of having a high-grade point average (OR = 1.6, p = 0.08). CONCLUSION: The results of this study support the available literature, indicating a correlation between study habits and high academic performance. Further multicenter studies are warranted to differentiate between high-achieving students and their peers using qualitative, semi-structured interviews. Educating the students about healthy study habits and enhancing their learning skills would also be of value.

Bridge plating is an effective adjunct treatment for complex elbow instability.

BACKGROUND: Managing persistent elbow instability and chronic dislocations presents challenges despite traditional treatments. Supplementary methods like immobilization and various fixations, though common, can carry high complication rates. This study assesses the efficacy of bridge plating in treating complex elbow instability through a retrospective review of patients. Data on characteristics, treatment duration, range of motion, complications, and evaluation scores were analyzed, providing insights into outcomes complications associated with bridge plating. RESULTS: Eleven patients were reviewed at a mean follow-up of 80 ± 68 weeks postoperatively. The mean age was 53 ± 14 years and there were 5 females and 6 males. The mean body mass index was 38. Bridge plating was used for a spectrum of complex elbow injuries. The mean time from injury to bridge plating in acute cases was 29 ± 19 days and 344 ± 381 days in chronic cases. The mean duration of bridge plating was 121 ± 72 days. At the time of plate removal, mean intraoperative elbow motion was extension 58° ± 12°, flexion 107° ± 14°, supination 66° ± 23° and pronation 60° ± 26°. At the latest follow-up visit, mean elbow motion was extension 37° ± 22°, flexion 127° ± 17°, supination 72° ± 15°, and pronation 63° ± 18°. There were 6 complications (55%): heterotopic ossification, ulnar neuropathy, wound failure over the plate in a thin patient, an ulnar shaft periprosthetic fracture due to a seizure-induced fall, and persistent elbow subluxation despite bridge plate fixation. Finally, 1 patient sustained a fracture of a 3.5-mm locking bridge plate. One patient required a contracture release for persistent stiffness. Four of these complications can be directly attributed to the use of the bridge plate (36%). At final follow-up, the mean patient-rated elbow evaluation score was 34, with 0 indicating no pain and disability. The mean Single Assessment Numeric Evaluation score was 66% for the 8 patients who had this available, with 100% being the best possible attainable score. CONCLUSION: Bridge plating effectively maintains joint reduction in selected complex elbow instability cases. However, patients with bridge plates often require a second surgery for removal and experience high rates of general complications because of the complexity of their condition.

Synthesis of millimeter-scale ZIF-8 single crystals and their reversible crystal structure changes.

Among various metal-organic frameworks (MOFs), the zeolitic imidazole framework (ZIF), constructed by the regular arrangement of 2-methylimidazole and metal ions, has garnered significant attention due to its distinctive crystals and pore structures. Variations in the sizes and shapes of ZIF crystals have been reported by changing the synthesis parameters, such as the molar ratios of organic ligands to metal ions, choice of solvents, and temperatures. Nonetheless, the giant ZIF-8 single crystals beyond the typical range have rarely been reported. Herein, we present the synthesis of millimeter-scale single crystal ZIF-8 using the solvothermal method in N,N-diethylformamide. The resulting 1-mm single crystal is carefully characterized through N2 adsorption-desorption isotherms, scanning electron microscopy, and other analytical techniques. Additionally, single-crystal X-ray diffraction is employed to comprehensively investigate the framework's mobility at various temperatures.

Millimeter-sized ZIF-8 single crystals were synthesized using the solvothermal method. These crystals exhibit a notable BET surface area of 1681 m²âˆ™g⁻¹ and demonstrate a reversible change in their crystal structure.

Left ventricular unloading in patients supported with veno-arterial extra corporeal membrane oxygenation; an international EuroELSO survey.

INTRODUCTION: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) improves end-organ perfusion in cardiogenic shock but may increase afterload, which can limit cardiac recovery. Left ventricular (LV) unloading strategies may aid cardiac recovery and prevent complications of increased afterload. However, there is no consensus on when and which unloading strategy should be used. METHODS: An online survey was distributed worldwide via the EuroELSO newsletter mailing list to describe contemporary international practice and evaluate heterogeneity in strategies for LV unloading. RESULTS: Of 192 respondents from 43 countries, 53% routinely use mechanical LV unloading, to promote ventricular recovery and/or to prevent complications. Of those that do not routinely unload, 65% cited risk of complications as the reason. The most common indications for unplanned unloading were reduced arterial line pulsatility (68%), pulmonary edema (64%) and LV dilatation (50%). An intra-aortic balloon pump was the most frequently used device for unloading followed by percutaneous left ventricular assist devices. Echocardiography was the most frequently used method to monitor the response to unloading. CONCLUSIONS: Significant variation exists with respect to international practice of ventricular unloading. Further research is required that compares the efficacy of different unloading strategies and a randomized comparison of routine mechanical unloading versus unplanned unloading.

Waste management in primary healthcare centers in Saudi Arabia: a policy analysis.

Medical waste poses high risks to healthcare workers, patients, the environment, and public health. Governments have adopted measures and enacted policies to ensure proper medical waste management. Through a retrospective policy analysis, we analyzed the waste management policy for primary healthcare centers in Saudi Arabia. By adopting Walt and Gilson's health policy analysis framework, we conducted a thematic analysis of documents to analyze the policy context, process, actors, and content. Contextual factors including accreditation, the Saudi Vision-2030 and the healthcare transformation plan contributed to the development of the policy. The policy was adapted from a regional policy that was enacted about 15 years ago. The policy content overlooked components relevant to the specific context of primary healthcare centers. Lack of training and cooperation among stakeholders challenged successful implementation and thus compliance with the policy. Respective stakeholders must take further actions to ensure implementation fidelity and sustainability of the policy.

Benefit and potential risk: Effects of in ovo copper oxide nanoparticles supplementation on hatchability traits, organ weights and histological features of newly hatched chicks.

This investigation was directed to examine the influence of copper oxide nanoparticles (CuO-NPs) on the hatchability traits, and chick quality of newly hatched broiler chicks. A total of 480 eggs were randomly divided into four treatment groups, each consisting of three duplicates. As a negative control (NC), the first group was not injected; the second group was injected with saline and served as a positive control (PC), the third and fourth groups were injected with 30 and 60 ppm of (CuO-NPs)/egg. Eggs were injected into the amniotic fluid on the eighteenth day of the incubation period. Results showed that the hatchability, chick yield %, yolk free-body mass (YFBM), chick length, shank length (SL), and relative weight of the heart, gizzard and intestine of day-old broiler chicks were all unaffected by the in ovo injection of CuO-NPs. The Pasgar Score was slightly improved compared to the NC and PC groups. Also, the in ovo administration of CuO-NPs (60 ppm/egg) significantly increased the intestine length. Both levels of CuO-NPs significantly increased the concentration of Cu ions in the hepatic tissue. Additionally, different levels of tissue damage were seen in the liver of the birds that were given low or high dosages of CuO-NPs. Conclusively, the in ovo injection of CuO-NPs has a good result on the appearance of the chicks (Pasgar score). However, negative effect of CuO-NPs on liver tissue may raise concerns about the potential risks of applying CuO-NPs in ovo administration.

Pesticidal Toxicity of Phosphine and Its Interaction with Other Pest Control Treatments.

Phosphine is the most widely used fumigant for stored grains due to a lack of better alternatives, all of which have serious shortcomings that restrict their use. The extensive use of phosphine has led to the development of resistance among insect pests of grain, which threatens its status as a reliable fumigant. Understanding the mode of action of phosphine as well as its resistance mechanisms provides insight that may lead to improved phosphine efficacy and pest control strategies. The mechanisms of action in phosphine vary from disrupting metabolism and oxidative stress to neurotoxicity. Phosphine resistance is genetically inherited and is mediated by the mitochondrial dihydrolipoamide dehydrogenase complex. In this regard, laboratory studies have revealed treatments that synergistically enhance phosphine toxicity that may be used to suppress resistance development and enhance efficacy. Here, we discuss the reported phosphine modes of action, mechanisms of resistance and interactions with other treatments.

Design and cytotoxic evaluation via apoptotic and antiproliferative activity for novel 11(4-aminophenylamino)neocryptolepine on hepatocellular and colorectal cancer cells.

The current study evaluated the cytotoxic activity of 11(4-Aminophenylamino)neocryptolepine (APAN), a novel derivative of neocryptolepine, on hepatocellular (HepG2) and colon (HCT-116) carcinoma cell lines as well as, the possible molecular mechanism through which it exerts its cytotoxic activity. The APAN was synthesized and characterized based on their spectral analyses. Scanning for anticancer target of APAN by Swiss software indicated that APAN had highest affinity for protein tyrosine kinase 6 enzyme. Furthermore, Super pred software indicated that APAN can be indicated in hepatic and colorectal cells with 92%. Molecular docking studies indicated that the binding affinity scores of APAN for protein PDB code: 6CZ4 of tyrosine kinase 6 recorded of - 6.6084 and RMSD value of 0.8891°A, while that for protein PDB: 7JL7 of caspase 3 was - 6.1712 and RMSD of 0.8490°A. Treatment of HepG2 and HCT-116 cells with APAN induced cytotoxicity with IC50 of 2.6 and 1.82 µg/mL respectively. In addition, it induced injury and serious morphological changes in cells including, disappearance of microvilli, membrane blebbing, cytoplasmic condensation, and shrunken nucleus with more condensed chromatin. Moreover, APAN significantly increased protein expression of annexin V (apoptotic marker). Furthermore, APAN significantly increased protein expression of caspase 3 and P53. However, it significantly reduced secretion of VEGF protein into the medium and decreased protein expression of PCNA and Ki67 in HepG2 and HCT-116 cells. This study indicated that APAN had cytotoxic activity against HepG2 and HCT-116 cells via increasing the expression of apoptotic proteins and reducing the expression of proliferative proteins.

Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial.

BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). PATIENTS AND METHODS: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. RESULTS: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. CONCLUSIONS: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.