AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5.

The mitochondrial intermembrane space protein AIFM1 has been reported to mediate the import of MIA40/CHCHD4, which forms the import receptor in the mitochondrial disulfide relay. Here, we demonstrate that AIFM1 and MIA40/CHCHD4 cooperate beyond this MIA40/CHCHD4 import. We show that AIFM1 and MIA40/CHCHD4 form a stable long-lived complex in vitro, in different cell lines, and in tissues. In HEK293 cells lacking AIFM1, levels of MIA40 are unchanged, but the protein is present in the monomeric form. Monomeric MIA40 neither efficiently interacts with nor mediates the import of specific substrates. The import defect is especially severe for NDUFS5, a subunit of complex I of the respiratory chain. As a consequence, NDUFS5 accumulates in the cytosol and undergoes rapid proteasomal degradation. Lack of mitochondrial NDUFS5 in turn results in stalling of complex I assembly. Collectively, we demonstrate that AIFM1 serves two overlapping functions: importing MIA40/CHCHD4 and constituting an integral part of the disulfide relay that ensures efficient interaction of MIA40/CHCHD4 with specific substrates.

Proteasomal degradation induced by DPP9-mediated processing competes with mitochondrial protein import.

Plasticity of the proteome is critical to adapt to varying conditions. Control of mitochondrial protein import contributes to this plasticity. Here, we identified a pathway that regulates mitochondrial protein import by regulated N-terminal processing. We demonstrate that dipeptidyl peptidases 8/9 (DPP8/9) mediate the N-terminal processing of adenylate kinase 2 (AK2) en route to mitochondria. We show that AK2 is a substrate of the mitochondrial disulfide relay, thus lacking an N-terminal mitochondrial targeting sequence and undergoing comparatively slow import. DPP9-mediated processing of AK2 induces its rapid proteasomal degradation and prevents cytosolic accumulation of enzymatically active AK2. Besides AK2, we identify more than 100 mitochondrial proteins with putative DPP8/9 recognition sites and demonstrate that DPP8/9 influence the cellular levels of a number of these proteins. Collectively, we provide in this study a conceptual framework on how regulated cytosolic processing controls levels of mitochondrial proteins as well as their dual localization to mitochondria and other compartments.

Language complexity modulates 8- and 10-year-olds' success at using their theory of mind abilities in a communication task.

Basic competence in theory of mind is acquired during early childhood. Nonetheless, evidence suggests that the ability to take others' perspectives in communication improves continuously from middle childhood to the late teenage years. This indicates that theory of mind performance undergoes protracted developmental changes after the acquisition of basic competence. Currently, little is known about the factors that constrain children's performance or that contribute to age-related improvement. A sample of 39 8-year-olds and 56 10-year-olds were tested on a communication task in which a speaker's limited perspective needed to be taken into account and the complexity of the speaker's utterance varied. Our findings showed that 10-year-olds were generally less egocentric than 8-year-olds. Children of both ages committed more egocentric errors when a speaker uttered complex sentences compared with simple sentences. Both 8- and 10-year-olds were affected by the demand to integrate complex sentences with the speaker's limited perspective and to a similar degree. These results suggest that long after children's development of simple visual perspective-taking, their use of this ability to assist communication is substantially constrained by the complexity of the language involved.

Beyond the discomfort: understanding and managing sexual pain in women, a comprehensive case-based discussion.

INTRODUCTION: Sexual pain has a profound impact on individuals, regardless of their sexual orientation or gender identity, and affects women more often than men. It adversely affects both sexual function and interpersonal relationships. Despite its prevalence, sexual pain in women often remains unaddressed and untreated. Various underlying causes contribute to sexual pain, sometimes involving multiple factors. We explore treatment options and offer clinical insights into the evaluation and management of 4 common conditions which cause sexual pain in women. In this article, we use the term "women" to indicate cisgender women. OBJECTIVES: Our aim is to highlight the most common clinical scenarios of sexual pain and provide comprehensive discussions on each, to improve patient care and outcomes in the management of sexual pain. METHODS: We conducted a comprehensive review of literature and clinical cases to explore the various causes and management strategies for sexual pain in women. We systematically searched databases such as PubMed, Google Scholar, and relevant medical journals. We included peer-reviewed articles, case studies, and clinical trials published between 2000 and 2023. Additionally, we analyzed real-life cases from our clinical practice at our academic institution. RESULTS: Our review identified various factors contributing to sexual pain in women, ranging from hormonal imbalances to neuroproliferative and inflammatory conditions affecting the genitourinary system. Each case should be approached individually to offer optimal management strategies accordingly. CONCLUSION: The management of sexual pain in women requires a comprehensive approach that addresses the multifactorial nature of the condition. Patient education and counseling play a crucial role in the management of sexual pain, empowering individuals to advocate for their own health and well-being. The collaboration between healthcare providers and patients can improve our understanding and management of this complex condition.

Biosynthesized Silver Nanoparticles from Cyperus Conglomeratus Root Extract Inhibit Osteogenic Differentiation of Immortalized Mesenchymal Stromal Cells.

BACKGROUND: Silver nanoparticles (AgNPs) are a focus of huge interest in biological research, including stem cell research. AgNPs synthesized using Cyperus conglomeratus root extract have been previously reported but their effects on mesenchymal stromal cells have yet to be investigated. OBJECTIVES: The aim of this study is to investigate the effects of C. conglomeratus-derived AgNPs on adipogenesis and osteogenesis of mesenchymal stromal cells. METHODS: AgNPs were synthesized using C. conglomeratus root extract, and the phytochemicals involved in AgNPs synthesis were analyzed using gas chromatography-mass spectrometry (GC-MS). The cytotoxicity of the AgNPs was tested on telomerase-transformed immortalized human bone marrow-derived MSCs-hTERT (iMSC3) and human osteosarcoma cell line (MG-63) using MTT and apoptosis assays. The uptake of AgNPs by both cells was confirmed using inductively coupled plasma-optical emission spectrometry (ICP-OES). Furthermore, the effect of AgNPs on iMSC3 adipogenesis and osteogenesis was analyzed using stain quantification and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RESULTS: The phytochemicals predominately identified in both the AgNPs and C. conglomeratus root extract were carbohydrates. The AgNP concentrations tested using MTT and apoptosis assays (0.5-64 µg/ml and 1,4 and 32 µg/ml, respectively) showed no significant cytotoxicity on iMSC3 and MG-63. The AgNPs were internalized in a concentration-dependent manner in both cell types. Additionally, the AgNPs exhibited a significant negative effect on osteogenesis but not on adipogenesis. CONCLUSION: C. conglomeratus-derived AgNPs had an impact on the differentiation capacity of iMSC3. Our results indicated that C. conglomeratus AgNPs and the associated phytochemicals could exhibit potential medical applications.

Insights into cryopreservation, recovery and genetic stability of medicinal plant tissues.

Several plant secondary metabolites are used in the production of different pharmaceuticals based on their biological activities. The conservation and sustainable use of medicinal plants is important for the industrial production of plant-based medicines. Different cryopreservation methods are used for long-term culture preservation, which allows fast regeneration of the preserved plant material with the maintenance of its primary original traits. These methods could ensure the sustainable indefinite supply of plant tissues for theoretically unlimited periods of time, and have gained considerable attention in recent years. It is important to assess the recovery rate and the genetic stability of the recovered plant tissues after cryopreservation because cryopreservation efficiency differs among plant tissues and species. This review lays particular emphasis on the pharmaceutical applications of plant secondary metabolites that are produced through tissue culture approaches, highlighting the methods used for their cryopreservation, as well as their recovery and genetic stability.

Autosomal recessive IL12RB1 mutation: A case report of a Sudanese child and his father.

Introduction: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare inherited condition characterized by selective susceptibility to weakly virulent mycobacteria, such as substrains of the bacille Calmette-Guérin (BCG) vaccine and different environmental mycobacteria. Case presentation: A 7-year-old Sudanese boy was referred to the immunology clinic with a suspected diagnosis of MSMD. This followed multiple presentations with disseminated tuberculosis and typhoid fever. Genetic testing surprisingly revealed pathogenic homozygous variants in IL12RB1 Exon 9, c.913A>T (p. Lys305*) in both the patient and his father, with a completely healthy asymptomatic carrier mother who is not blood related to the patient's father. Conclusion: It is challenging to diagnose MSMD, especially in developing countries where health systems are poor and have limited resources. Family history and genetic tests may help in early MSMD treatment and avoiding disease complications.

Phenolic Contents and Antioxidant Activity of Citrullus colocynthis Fruits, Growing in the Hot Arid Desert of the UAE, Influenced by the Fruit Parts, Accessions, and Seasons of Fruit Collection.

Citrullus colocynthis (Cucurbitaceae) is an important medicinal plant traditionally used in the United Arab Emirates (UAE). In a recent study, it has been reported that different individuals of the same population of C. colocynthis, growing in the hot arid desert of the UAE, exhibited variations in their fruit size, color, and stripe pattern. In addition, these plants differed genetically, and their seeds showed variation in size, color, and germination behavior (hereinafter, these individuals are referred to as accessions). In the present study, the total phenolic content (TPC) and antioxidant activity of different fruit parts (rinds, pulps, and seeds) of three different accessions with significant genetic variations, from a single C. colocynthis population, were assessed in response to different seasonal environments. Green fruits were collected in summer and winter from three accessions growing in the botanic garden of the University of Sharjah, UAE. Methanolic extracts from different fruit parts were prepared. The TPC was qualitatively determined by a Folin-Ciocalteu assay, while the antioxidant capacity was analyzed using the 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical scavenging ability. The metabolic profiling of the antioxidant metabolites was determined using a gas chromatograph coupled to mass spectrometry (GC-MS), associated with a literature search. The results showed that the TPC and the DPPH free radical scavenging activity varied between seasons, accessions, and fruit parts. The highest phenolics were in rinds, but the highest antioxidant activities were in seeds during the summer, reflecting the role of these compounds in protecting the developed seeds from harsh environmental conditions. The metabolomic analysis revealed the presence of 28 metabolites with significant antioxidant activities relevant to fruit parts and season. Collectively, the formation of phenolics and antioxidant activity in different fruit parts is environmentally and genetically dependent.

Study of the elution of fluconazole from a self-polymerizing acrylic resin and its activity against resistant Candida albicans.

The study aimed, firstly, to monitor the release of an antifungal drug, fluconazole, from a self-polymerizing poly(methyl methacrylate) (PMMA) denture base resin in artificial saliva and comparing it with the release in water; and secondly, to investigate the effect of the released drug on the growth of resistant and standard strains of Candida albicans. A high-performance liquid chromatography-ultra-violet (HPLC-UV) method was used in the analysis of the released eluates into distilled water from self-polymerized PMMA discs doped with the 10% fluconazole antifungal drug. The efficacy of the released drug against resistant and standard strains of C. albicans was monitored, using agar diffusion method. The results showed that fluconazole, can be successfully incorporated with the self-polymerized PMMA. The findings suggest that the drug leaches steadily out of the PMMA resin into artificial saliva and distilled water at mouth temperature and that sustained drug release continued throughout the 28 days test period. It was shown that the released drug demonstrated antifungal activity against both standard and resistant C. albicans. The findings of this investigation have a clinical value in terms of their significant contribution to the treatment of fungal infections of the oral cavity. The sustained release of antifungal drug from the PMMA resin clearly constitutes a new dosage form of the drug via the poly(methyl methacrylate) delivery system.

Simultaneous Pancreas-Kidney Transplant: A Positive Stimulus in the Medical World.

Kidneys are one of the essential organs of our body, with chronic kidney disease being a very prevalent and emotionally, mentally and physically straining condition affecting 1 in 15 people worldwide. The prevalence is further escalating with every passing year. It is slowly progressive in nature, and many times goes unnoticed until symptoms start manifesting and presenting themselves much later in life. In this article, end-stage renal disease (ESRD) due to diabetes mellitus and its effect on different organs is examined, along with the role of simultaneous pancreas-kidney transplant (SPKT) in the management of this condition. Although proven to be an assured treatment with an outstanding allograft acceptance rate, the fact that it is still not widely adopted in many healthcare setups due to financial implications is also studied. Online databases such as PubMed and Google Scholar were searched for the purpose of data collection; due to the very limited number of randomized controlled trials conducted on this given topic, a limited discussion was retrieved. By applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method and several inclusion/exclusion criteria, approximately 66 articles were assessed for eligibility based on the title and abstract. A total of 44 articles were shortlisted and considered in the final review. Several systematic reviews that have been conducted in the past reveal the importance of SPKT at an early stage of diagnosis towards increasing longevity of the patient with freedom from multiple medications. Transplant is a cost-effective therapy when compared to the prolonged dependence on dialysis, insulin pens, and increased susceptibility to infections. A greater number of specialists must also train to carry out SPKT and identify the early stages of ESRD, and medical centers should be encouraged to carry out transplant procedures effectively both financially and medically. This can be achieved through the development of global policy mechanisms and establishment of universally adoptable standards.

Spinal accessory neuropathy associated with deep tissue massage: a case report.

Spinal accessory neuropathy (SAN) causes impaired arm mobility and pain. The spinal accessory nerve is often injured during surgical procedures such as neck dissection for tumor resection or cervical lymph node biopsy. Other traumatic injuries may also occur. SAN causes weakness of the trapezius muscle and, less frequently, of the sternocleidomastoid muscle. The clinical consequence of trapezius muscle weakness includes impaired stability of the scapula leading to upper limb dysfunction and pain. We present a rare and illustrative case of SAN associated with deep tissue massage leading to scapular winging and droopy shoulder as a result of weakness of the trapezius muscle.

Exogenous Production of Silver Nanoparticles by Tephrosia apollinea Living Plants under Drought Stress and Their Antimicrobial Activities.

Nanoparticle (NP) synthesis by biological systems is more cost-effective, safe, and environmentally friendly when compared to currently used chemical and physical methods. Although many studies have utilized different plant extracts to synthesize NPs, few studies have incorporated living plants. In this study, silver nanoparticles (AgNPs) were synthesized exogenously by Tephrosia apollinea living plant system under the combined stresses of silver nitrate and different levels of drought stress simulated by Polyethylene glycol (PEG) (0, -0.1, -0.2, and -0.4 MPa for three and six days). Biomass, cell death, and H2O2 content were evaluated to determine the toxicological effect of the treatments on the plant. More severe effects were detected in day 6 plants compared to day 3 plants, and at higher drought levels. UV-visible spectrum, energy dispersive X-ray spectroscopy, X-ray diffraction, scanning electron microscope, and Fourier transform infrared spectroscopy were used to detect and characterize the T. apollinea synthesized NPs. The shapes of the NPs were spherical and cubic with different phytochemicals being the possible capping agents. Broth microdilution was used to determine the antimicrobial activity of the NPs against Escherichia coli and Staphylococcus aureus. In this case, antimicrobial activity increased at higher PEG concentrations. Bactericidal effects were observed against E. coli, while only bacteriostatic effects were detected against S. aureus.

Vectorial Import via a Metastable Disulfide-Linked Complex Allows for a Quality Control Step and Import by the Mitochondrial Disulfide Relay.

Disulfide formation in the mitochondrial intermembrane space (IMS) is an essential process. It is catalyzed by the disulfide relay machinery, which couples substrate import and oxidation. The machinery relies on the oxidoreductase and chaperone CHCHD4-Mia40. Here, we report on the driving force for IMS import and on a redox quality control mechanism. We demonstrate that unfolded reduced proteins, upon translocation into the IMS, initiate formation of a metastable disulfide-linked complex with CHCHD4. If this interaction does not result in productive oxidation, then substrates are released to the cytosol and degraded by the proteasome. Based on these data, we propose a redox quality control step at the level of the disulfide-linked intermediate that relies on the vectorial nature of IMS import. Our findings also provide the mechanistic framework to explain failures in import of numerous human disease mutants in CHCHD4 substrates.

The mitochondrial oxidoreductase CHCHD4 is present in a semi-oxidized state in vivo.

Disulfide formation in the mitochondrial intermembrane space is an essential process catalyzed by a disulfide relay machinery. In mammalian cells, the key enzyme in this machinery is the oxidoreductase CHCHD4/Mia40. Here, we determined the in vivo CHCHD4 redox state, which is the major determinant of its cellular activity. We found that under basal conditions, endogenous CHCHD4 redox state in cultured cells and mouse tissues was predominantly oxidized, however, degrees of oxidation in different tissues varied from 70% to 90% oxidized. To test whether differences in the ratio between CHCHD4 and ALR might explain tissue-specific differences in the CHCHD4 redox state, we determined the molar ratio of both proteins in different mouse tissues. Surprisingly, ALR is superstoichiometric over CHCHD4 in most tissues. However, the levels of CHCHD4 and the ratio of ALR over CHCHD4 appear to correlate only weakly with the redox state, and although ALR is present in superstoichiometric amounts, it does not lead to fully oxidized CHCHD4.

Using DNA Barcoding to Detect Adulteration in Different Herbal Plant- Based Products in the United Arab Emirates: Proof of Concept and Validation.

BACKGROUND: Commercially available herbal and medicinal plants-based products are susceptible to substitution or contamination with other unlabeled or undesired materials. This will reduce the quality of the product, and may lead to intoxication and allergy. METHODS: DNA barcoding is a molecular technology that allows the identification of plant materials at the species level, by sequencing short stretches of standardized gene sequences from nuclear or organelle genome in an easy, rapid, accurate and cost-effective manner. The aim of this research is to apply DNA barcoding to investigate the authenticity of commercially available herbal and medicinal plant-based products within the UAE markets. A total of 30 samples were analyzed, covering six different herbal products (thyme, cardamom, anise, basil, turmeric, and ginger), obtained in fresh and dried forms. DNA was extracted and three barcode loci including (rbcL), (matK) and (ITS) were amplified, sequenced and analyzed by BLAST. RESULTS: In terms of amplification efficiency, the results suggest that rbcL is the most suitable marker for species identification giving 75% of successful amplification, followed by ITS with 66.67%, whereas matK had the lowest with 18.52%. Adulteration was detected in two samples, ginger powder and dry thyme leave samples. The adulterants were from Triticum and Oryza genera. CONCLUSION: Clearly, the results from this report provide evidence that DNA barcoding technique is efficient in the recognition of commercial plant products. Thus, it can be considered as a fast, effective, and reliable method to detect adulteration in plant-based products in the UAE market.

Socio-economic determinants of smoking among Iraqi adults: Data from Non-Communicable Risk Factor STEPS survey 2015.

AIM: Highlight the socio-economic determinants of smoking among Iraqi adults aged (18+) years. METHOD: The study is derived from Non-Communicable Diseases Risk Factors STEPS survey Iraq 2015. A cross-sectional survey conducted among households from 15 Iraqi governorates. Nainawa, Salahaddin and Al-Anbar were excluded for unstable conditions. Multi-stage cluster sampling technique used to include 4120 Iraqi adults. Interviews started from the first week of November for 20 days using Arabic and Kurdish translated versions of STEPS questionnaire, at last 4071 valid questionnaire forms were gathered. RESULTS: Among men, smoking rates decline with age, 18-39 years (OR: 1.74; 95%CI: 1.22-2.47) and 40-59 years (OR: 1.69; 95%CI: 1.18-2.44) compared to elderly. They also decline as education level increased, No schooling (OR: 2.74; 95%CI: 1.75-4.31), Less than primary school (OR: 2.46; 95%CI: 1.68-3.62), Primary school (OR: 2.15; 95%CI: 1.51-3.05) and Secondary school (OR: 1.99; 95%CI: 1.33-2.99). They were higher among non-governmental (OR: 1.58; 95%CI: 1.03-2.44) and self-employee (OR: 1.4; 95%CI: 1.06-1.84). The lowest smoking rates were found among women aged 18-39 years (OR: 0.34; 95%CI: 0.14-0.86). While the highest rates were found among self-employed women (OR: 5.3; 95%CI: 1.12-25.06). CONCLUSIONS: Tobacco smoking was higher among men aged less than 40 years, low educated as well as non-governmental and self-employed people. While it was higher among elderly and self-employed women.

Breast cancer-related lymphedema.

Every year in the United States, breast cancer is diagnosed in more than 200,000 women. Because of the prevalence of breast cancer, treatment-related sequelae are of Importance to many survivors of the disease. One such sequela is upper extremity lymphedema, which occurs when fluid accumulates in the Interstitial space and causes enlargement and usually a feeling of heaviness in the limb. Axillary surgery contributes considerably to the incidence of lymphedema, with the incidence and severity of swelling related to the number of lymph nodes removed. Lymphedema after standard axillary lymph node dissection can occur in up to approximately 50% of patients. However, the risk of lymphedema is decreased substantially with newer sentinel lymph node sampling procedures. Adjuvant radiotherapy to the breast or lymph nodes increases the risk of lymphedema, which has been reported in 9% to 40% of these patients. Management of lymphedema requires a multidisciplinary approach to minimize the effect on the patient's quality of life. This review presents an overview of the pathophysiology, diagnosis, prevention, and treatment of breast cancer-related lymphedema.

Cystic Fibrosis in a Female Infant with Cardiac, Ocular, and Musculoskeletal Anomalies.

Cystic fibrosis (CF) remains the most common hereditary disease in the western population. Its concomitant presence with other congenital abnormalities is a rare phenomenon with very little documentation. In this case report we describe a case of cystic fibrosis in a female infant with cardiac, ocular, and musculoskeletal abnormalities. A brief literature review is also provided.

Major depressive disorder and type II diabetes mellitus: mechanisms underlying risk for Alzheimer's disease.

UNLABELLED: Objectives/Introduction: Major Depressive Disorder is associated age-related medical conditions (e.g., diabetes mellitus type II, Alzheimer's disease) that frequently manifest at an earlier age, contributing to excess and premature mortality. The foregoing observation provides the impetus to further refine potential mechanisms and molecular pathways subserving these disorders in order to more effectively treat these clinical populations by aiming to reduce and prevent cognitive impairment as well as downstream neurodegeneration. METHODS: A review of computerized databases was performed to identify original studies that investigated the impact of the independent and comorbid association of major depressive disorder and type II diabetes mellitus on cognitive function and conversion to Alzheimer's disease. English-written articles were selected for review based on the adequacy of sample size, the use of standardized diagnostic instruments, and validated assessment measures. RESULTS: Individuals with persistent neuropsychiatric illness account for a disproportionate overall burden of disability mediated largely by decrements in cognitive performance. Mixed results from epidemiological and clinical studies suggest that insulin may mediate and/or moderate risk for cognitive dysfunction in subsets of individuals. Moreover, physiological changes, such as insulin resistance and the activation of neuroimmunoinflammatory systems result in glial and neuroendangerment. CONCLUSION: Disturbances in the metabolic milieu exert a neurotoxic effect on the central nervous system and poses a hazard to other organ systems.

Management of 2 teeth diagnosed with dens invaginatus with regenerative endodontics and apexification in the same patient: a case report and review.

INTRODUCTION: This review and case report present the treatment of a 10-year-old boy with both permanent maxillary lateral incisors demonstrating Oehlers type II dens invaginatus and pulpal involvement. Treatment was complicated by dental anxiety, supraventricular tachycardia, immature tooth development, and facial cellulitis. METHODS: An infected necrotic pulp of the permanent maxillary left lateral incisor was treated by apexification and endodontic treatment with mineral trioxide aggregate. The necrotic pulp of the permanent maxillary right lateral incisor was treated with canal debridement and dressing under general anesthesia. RESULTS: Periapical healing of both teeth occurred, with the right lateral incisor showing continued root growth, thickening of the dentinal root walls, and completed apex formation. This tooth responded normally to pulp testing. Twenty-eight months after initial treatment, the right lateral incisor displayed progressive sclerosis of the canal. CONCLUSIONS: This case demonstrates possible pulpal regeneration of an infected maxillary right lateral incisor with dens invaginatus and an immature apex after minimal canal debridement.