Enhancing kernel oil and tailoring fatty acid composition by genomics-assisted selection for dgat1-2 and fatb genes in multi-nutrient-rich maize: new avenue for food, feed and bioenergy.

Enhancing maize kernel oil is vital for improving the bioavailability of fat-soluble vitamins. Here, we combined favourable alleles of dgat1-2 and fatb into parental lines of four multi-nutrient-rich maize hybrids (APTQH1, APTQH4, APTQH5 and APTQH7) using marker-assisted selection (MAS). Parental lines possessed favourable alleles of crtRB1, lcyE, vte4 and opaque2 genes. Gene-specific markers enabled successful foreground selection in BC1F1, BC2F1 and BC2F2, while background selection using genome-wide microsatellite markers (127-132) achieved 93% recurrent parent genome recovery. Resulting inbreds exhibited significantly higher oil (6.93%) and oleic acid (OA, 40.49%) and lower palmitic acid (PA, 14.23%) compared to original inbreds with elevated provitamin A (11.77 ppm), vitamin E (16.01 ppm), lysine (0.331%) and tryptophan (0.085%). Oil content significantly increased from 4.80% in original hybrids to 6.73% in reconstituted hybrids, making them high-oil maize hybrids. These hybrids displayed 35.70% increment in oil content and 51.56% increase in OA with 36.32% reduction in PA compared to original hybrids, while maintaining higher provitamin A (two-fold), vitamin E (nine-fold), lysine (two-fold) and tryptophan (two-fold) compared to normal hybrids. Lipid health indices showed improved atherogenicity, thrombogenicity, cholesterolaemic, oxidability, peroxidizability and nutritive values in MAS-derived genotypes over original versions. Besides, the MAS-derived inbreds and hybrids exhibited comparable grain yield and phenotypic characteristics to the original versions. The maize hybrids developed in the study possessed high-yielding ability with high kernel oil and OA, low PA, better fatty acid health and nutritional properties, higher multi-vitamins and balanced amino acids, which hold immense significance to address malnutrition and rising demand for oil sustainably in a fast-track manner.

Germline ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition.

The genomics era has facilitated discovery of new genes predisposing to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ERG as a novel autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor critical for definitive hematopoiesis, stem cell function and platelet maintenance. ERG colocalizes with other transcription factors including RUNX1 and GATA2 on promoters/enhancers of genes orchestrating hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 thrombocytopenic individuals from one family and 14 additional ERG variants in unrelated individuals with BMF/HM including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germline ERG variants included cytopenias (thrombocytopenia, neutropenia, pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense, 1 truncating) including 3 missense population variants were functionally characterized. Thirteen potentially pathogenic ETS domain missense variants displayed loss-of-function characteristics disrupting transcriptional transactivation, DNA-binding and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture, and to promote acute erythroleukemia when transplanted into mice, concordant with these variants being loss-of-function. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germline ERG variants has clinical implications for patient/family diagnosis, counselling, surveillance, and treatment strategies including selection of bone marrow donors or cell/gene therapy.

Efficient removal of cationic dyes using lemon peel-chitosan hydrogel composite: RSM-CCD optimization and adsorption studies.

The most prominent and easily identifiable factor of water purity is its colour, which may be both physically undesirable, and act as an alert towards potential environmental contamination. The current study describes the optimum synthesis technique for Lemon Peel-Chitosan hydrogel using the Response Surface Methodology integrated Central composite Design (RSM-CCD). This adsorbent is both environmentally friendly and cost-effective. The hydrogel exhibited a maximal dye removal capacity of 24.984, 24.788, 24.862, 23.483, 24.409, and 24.726 mg g-1, for 10 mg L-1 aqueous medium of Safranin O, Methylene blue, Basic fuchsin, Toluidine blue, Brilliant green and Crystal violet, respectively. The adsorption kinetics and isotherm data suggest that the Pseudo second-order kinetic and Freundlich adsorption isotherm models precisely represent the respective behaviour of all the dyes. The thermodynamic viability of the process is determined by the values of ΔG, ΔH, and ΔS. The probable mechanism of adsorption was the electrostatic interaction between the dye molecules and the hydrogel. The regenerated hydrogel had removal efficiencies of over 80 % even after enduring six cycles. Hence, the exceptional recyclability and utility of the adsorbent show their sustainability for wastewater treatment in textile factories.

Energizing Healing with Electromagnetic Field Therapy in Musculoskeletal Disorders.

There is mounting evidence to suggest that exogenous electromagnetic fields (EMF) may play a significant role in various biological processes that are crucial to therapeutic interventions. EMFs have been identified as a non-invasive, safe, and effective therapy that appears to have no apparent side effects. Numerous studies have demonstrated that pulsed EMFs (PEMFs) have the potential to become a stand-alone or adjunctive treatment modality for managing musculoskeletal disorders. However, several questions remain unresolved. Before their widespread clinical application, further research from well-designed, high-quality studies is required to standardize treatment parameters and determine the optimal protocol for healthcare decision-making. This article provides a comprehensive overview of the impact of musculoskeletal diseases on overall well-being, the limitations of conventional treatments, and the need to explore alternative therapeutic modalities such as electromagnetic field (EMF) therapy. EMF therapy uses low-frequency electromagnetic waves to stimulate tissue repair, reduce inflammation, and modulate pain signals, making it a safe and convenient alternative to conventional treatments. The article also discusses the historical perspective of EMF therapy in medicine. The article highlights the potential of EMF therapy as a personalized and comprehensive care option for musculoskeletal diseases, either alone or in conjunction with other therapies. It emphasizes the imperative for further research in this field and presents a compelling case for the use of EMF therapy in managing musculoskeletal diseases. Overall, the available findings on the underlying cellular and molecular biology support the use of EMF therapy as a viable option for the management of musculoskeletal disorders and stresses the need for continued research in this area.

Critical Assessment of the Neurological Complications during High-Risk Anesthesia Procedures.

Damage to the peripheral and central nervous systems is frequently irreversible. Surgically induced neurological damage and anesthesia may result in catastrophic situations for patients and their families. The incidence of significant neurological complications during the perioperative period is examined in this article. In contrast to other organs like the kidney, heart, liver, lungs, and skeletal system, native neurological function cannot be replaced with artificial parts or devices soon. Ignoring brain function during the perioperative period has been a systemic problem in anesthesiology, even though the central and peripheral nervous systems are crucial. This bold claim is intended to draw attention to the fact that, unlike the circulatory and respiratory systems, which have been routinely monitored for decades, the brain and other neural structures do not have a standard monitoring during surgery and anesthesia. Given that the brain and spinal cord are the principal therapeutic targets of analgesics and anesthetics, this deficiency in clinical care is even more alarming. Organs that are notoriously hard to repair or replace after damage have, up until now, received comparatively little attention. In this article, a succinct overview of five neurological complications associated with surgery and anesthesia is presented. After critically reviewing the literature on the subject, the article is focused to common (delirium), controversial (postoperative cognitive decline), and potentially catastrophic (stroke, spinal cord ischemia, or postoperative visual loss) adverse events in the neurological surgery setting. The findings will increase awareness of major neurological complications to the involved surgical and anesthesia team and enhance preventive and treatment strategies during the perioperative period.

Diabetes and Abdominal Aortic Aneurysm: Is the Protective Effect on AAA Due to Antidiabetic Medications Alone, Due to the Disease Alone, or Both?

Diabetes is a metabolic disease that may result in multiple microvascular and macrovascular diseases. Interestingly, many studies have demonstrated the inverse relationship between diabetes and the development and expansion of abdominal aortic aneurysm (AAA). One hypothesis is that the aortic wall stiffness resulting from hyperglycemia and advanced glycation end products could delay the development and growth of AAA. Other studies have proposed that the concurrent use of antidiabetic medications which promote anti-inflammatory cytokines while hindering pro-inflammatory cytokines may potentially be the reason for this protective effect of diabetes on AAA. Contrastingly, the presence of diabetes has been found to have a negative effect on the outcome of AAA following its repair which may be due to elevated blood glucose negatively affecting the healing process. The current literature has also demonstrated the negative impact of the use of fluoroquinolones on AAA. This comprehensive review critically reviewed and summarized the role of diabetes, anti-diabetes medications and fluoroquinolones on AAA, and on the effect of diabetes and certain anti-diabetes medications on outcomes following its repair.

Ethnic and Racial Disparities in Clinical Manifestations of Atopic Dermatitis.

Atopic dermatitis is a heterogenous inflammatory skin illness that may last for long time and affect people of different racial and ethnic backgrounds. The condition primarily appears in infants and young children. There are people living with atopic dermatitis in every country and every ethnic group, although the frequency of the disease varies greatly. Due to the varied clinical presentations that atopic dermatitis can have, it can be challenging to characterize and diagnose the disease, particularly in adults. Nevertheless, there exists a dearth of information pertaining to the various presentations of atopic dermatitis among individuals from diverse racial and cultural groups. This critical review article offers a succinct and comprehensive overview of the current findings on the epidemiology of atopic dermatitis with regards to ethnic and racial disparities. The findings hold potential significance in advancing the development of targeted treatments for personalized medicine approaches and enhancing the quality of life for patients with atopy.

Chronic Adaptation of Achilles Tendon Tissues upon Injury to Rotator Cuff Tendon in Hyperlipidemic Swine.

The biomechanical properties of the tendon are affected due to the changes in composition of the tendon extracellular matrix (ECM). Age, overuse, trauma and metabolic disorders are a few associated conditions that contribute to tendon abnormalities. Hyperlipidemia is one of the leading factors that contribute to the compromised biomechanical. Injury was made on infraspinatus tendon of hyperlipidemic swines. After 8 weeks (i) infraspinatus tendon from the injury site, (ii) infraspinatus tendon from the contralateral side and (iii) Achilles tendon, were collected and analyzed for ECM components that form the major part in biomechanical properties. Immunostaining of infraspinatus tendon on the injury site had higher staining collagen type-1 (COL1A1), biglycan, prolyl 4-hydroxylase and mohawk but lower staining for decorin than the control group. The Achilles tendon of the swines that had injury on infraspinatus tendon showed a chronic adaptation towards load which was evident from a more organized ECM with increased decorin, mohawk and decreased biglycan, scleraxis. The mechanism behind the collagen turnover and chronic adaptation to load need to be studied in detail with the biomechanical properties.

Understanding Fibrous Tissue in the Effective Healing of Rotator Cuff Injury.

The rotator cuff is a crucial group of muscles and tendons in the shoulder complex that plays a significant role in the stabilization of the glenohumeral joint and enabling a wide range of motion. Rotator cuff tendon tears can occur due to sudden injuries or degenerative processes that develop gradually over time, whether they are partial or full thickness. These injuries are common causes of shoulder pain and functional impairment, and their complex nature highlights the essential role of the rotator cuff in shoulder function. Scar formation is a crucial aspect of the healing process initiated following a rotator cuff tendon tear, but excessive fibrous tissue development can potentially lead to stiffness, discomfort, and movement limitations. Age is a critical risk factor, with the prevalence of these tears increasing among older individuals. This comprehensive review aims to delve deeper into the anatomy and injury mechanisms of the rotator cuff. Furthermore, it will inspect the signaling pathways involved in fibrous tissue development, evaluate the various factors affecting the healing environment, and discuss proactive measures aimed at reducing excessive fibrous tissue formation. Lastly, this review identifed gaps within existing knowledge to advance methods for better management of rotator cuff tendon injuries.

Epidemiology, Mechanisms and Prevention in the Etiology of Environmental Factor-Induced Cardiovascular Diseases.

Cardiovascular diseases are a significant cause of mortality worldwide, and their prevalence can be amplified by a range of environmental factors. This review article critically evaluated the published information on the epidemiology and pathophysiological mechanisms of various environmental factors such as air indoor and outdoor air pollution, water pollution, climate change, and soil pollution. Preventative measures to mitigate these effects including public health responses are discussed with gaps in our knowledge for future studies.

Epidemiology, Pathophysiology, and Treatment Strategies of Concussions: A Comprehensive Review.

A concussion is a particular manifestation of a traumatic brain injury, which is the leading cause of mortality and disabilities across the globe. The global prevalence of traumatic brain injury is estimated to be 939 instances per 100,000 individuals, with approximately 5.48 million people per year experiencing severe traumatic brain injury. Epidemiology varies amongst different countries by socioeconomic status with diverse clinical manifestations. Additionally, classifying concussions is an ambiguous process as clinical diagnoses are the only current classification method, and morbidity rates differ by demographic location as well as populations examined. In this article, we critically reviewed the pathophysiology of concussions, classification methods, treatment options available including both pharmacologic and nonpharmacologic intervention methods, etiologies as well as global etiologic differences associated with them, and clinical manifestations along with their associated morbidities. Furthermore, analysis of the current research regarding the incidence of concussion based traumatic brain injuries and future directions are discussed. Investigation on the efficacy of new therapeutic-related interventions such as exosome therapy and electromagnetic field stimulation are warranted to properly manage and treat concussion-induced traumatic brain injury.

Quantitative Assessment of Intracellular Effectors and Cellular Response in RAGE Activation.

The review delves into the methods for the quantitative assessment of intracellular effectors and cellular response of Receptor for Advanced Glycation End products (RAGE), a vital transmembrane receptor involved in a range of physiological and pathological processes. RAGE bind to Advanced Glycation End products (AGEs) and other ligands, which in turn activate diverse downstream signaling pathways that impact cellular responses such as inflammation, oxidative stress, and immune reactions. The review article discusses the intracellular signaling pathways activated by RAGE followed by differential activation of RAGE signaling across various diseases. This will ultimately guide researchers in developing targeted and effective interventions for diseases associated with RAGE activation. Further, we have discussed how PCR, western blotting, and microscopic examination of various molecules involved in downstream signaling can be leveraged to monitor, diagnose, and explore diseases involving proteins with unique post-translational modifications. This review article underscores the pressing need for advancements in molecular approaches for disease detection and management involving RAGE.

Hyperlipidemia Induced Pathological Changes with no Effect in Biomechanical Properties in the Achilles Tendon of Young Swine.

Hyperlipidemia is linked to atherosclerosis and various diseases. Its strong association with Achilles tendinopathies and xanthomas affects tendon properties through lipid deposition in tendon tissue. We examined the impact of hyperlipidemia on the biomechanical properties of the swine Achilles tendons. Swines were fed a high-cholesterol-high-fat diet to induce hyperlipidemia, and their Achilles tendons were collected and examined for biomechanical properties. The ultimate tensile strength, modulus of elasticity and viscoelastic properties did not exhibit significant differences between hyperlipidemic and control swines. H&E and pentachrome staining revealed extracellular matrix (ECM) disorganization and cellular infiltration in the hyperlipidemic swines, highlighting a marked difference between the control and hyperlipidemic groups. These results suggest hyperlipidemia in young swines alters the tendon composition and may contribute to weak biomechanical properties with time.

Targeting Oncostatin M Receptor to Attenuate Carotid Artery Plaque Vulnerability in Hypercholesterolemic Microswine.

Atherosclerosis is a chronic inflammatory disease that leads to acute embolism via the formation of atherosclerotic plaques. Plaque formation is first induced by fatty deposition along the arterial intima. Inflammation, bacterial infection, and the released endotoxins can lead to dysfunction and phenotypic changes of vascular smooth muscle cells (VSMCs), advancing the plaque from stable to unstable form and prone to rupture. Stable plaques are characterized by increased VSMCs and less inflammation while vulnerable plaques develop due to chronic inflammation and less VSMCs. Oncostatin M (OSM), an inflammatory cytokine, plays a role in endothelial cells and VSMC proliferation. This effect of OSM could be modulated by p27KIP1, a cyclin-dependent kinase (CDK) inhibitor. However, the role of OSM in plaque vulnerability has not been investigated. To better understand the role of OSM and its downstream signaling including p27KIP1 in plaque vulnerability, we characterized the previously collected carotid arteries from hyperlipidemic Yucatan microswine using hematoxylin and eosin stain, Movat Pentachrome stain, and gene and protein expression of OSM and p27KIP1 using immunostaining and real-time polymerase chain reaction. OSM and p27KIP1 expression in carotid arteries with angioplasty and treatment with either scrambled peptide or LR12, an inhibitor of triggering receptor expressed on myeloid cell (TREM)-1, were compared between the experimental groups and with contralateral carotid artery. The results of this study elucidated the presence of OSM and p27KIP1 in carotid arteries with plaque and their association with arterial plaque and vulnerability. The findings suggest that targeting OSM and p27KIP1 axis regulating VSMC proliferation may have therapeutic significance to stabilize plaque.

Transcriptional and Translational Regulation of Differentially Expressed Genes in Yucatan Miniswine Brain Tissues following Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of morbidity, disability, and mortality worldwide. Motor and cognitive deficits and emotional disturbances are long-term consequences of TBI. A lack of effective treatment for TBI-induced neural damage, functional impairments, and cognitive deficits makes it challenging in the recovery following TBI. One of the reasons may be the lack of knowledge underlying the complex pathophysiology of TBI and the regulatory factors involved in the cellular and molecular mechanisms of inflammation, neural regeneration, and injury repair. These mechanisms involve a change in the expression of various proteins encoded by genes whose expression is regulated by transcription factors (TFs) at the transcriptional level and microRNA (miRs) at the mRNA level. In this pilot study, we performed the RNA sequencing of injured tissues and non-injured tissues from the brain of Yucatan miniswine and analyzed the sequencing data for differentially expressed genes (DEGs) and the TFs and miRs regulating the expression of DEGs using in-silico analysis. We also compared the effect of the electromagnetic field (EMF) applied to the injured miniswine on the expression profile of various DEGs. The results of this pilot study revealed a few DEGs that were significantly upregulated in the injured brain tissue and the EMF stimulation showed effect on their expression profile.

Therapeutic Potential of Targeting p27kip1 in Plaque Vulnerability.

Atherosclerosis, a critical contributor to coronary artery diseases, involves the accumulation of cholesterol, fibrin, and lipids within arterial walls, inciting inflammatory reactions culminating in plaque formation. This multifaceted interplay encompasses excessive fibrosis, fatty plaque development, vascular smooth muscle cell (VSMC) proliferation, and leukocyte migration in response to inflammatory pathways. While stable plaques demonstrate resilience against complications, vulnerable ones, with lipid-rich cores, necrosis, and thin fibrous caps, lead to thrombosis, myocardial infarction, stroke, and acute cerebrovascular accidents. The nuanced phenotypes of VSMCs, modulated by gene regulation and environmental cues, remain pivotal. Essential markers like alpha-SMA, myosin heavy chain, and calponin regulate VSMC migration and contraction, exhibiting diminished expression during VSMC de-differentiation and proliferation. p27kip, a CDK inhibitor, shows promise in regulating VSMC proliferation and appears associated with TNF-α-induced pathways impacting unstable plaques. Oncostatin M (OSM), an IL-6 family cytokine, correlates with MMP upregulation and foam cell formation, influencing plaque development. Efforts targeting mammalian target of rapamycin (mTOR) inhibition, notably using rapamycin and its analogs, demonstrate potential but pose challenges due to associated adverse effects. Exploration of the impact of p27kip impact on plaque macrophages presents promising avenues, yet its complete therapeutic potential remains untapped. Similarly, while OSM has exhibited potential in inducing cell cycle arrest via p27kip, direct links necessitate further investigation. This critical review discusses the role of mTOR, p27kip, and OSM in VSMC proliferation and differentiation followed by the therapeutic potential of targeting these mediators in atherosclerosis to attenuate plaque vulnerability.

A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19.

Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the in vitro pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883. PF-07817883 also demonstrated oral efficacy in a mouse-adapted SARS-CoV-2 model at plasma concentrations equivalent to nirmatrelvir. The preclinical in vivo pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir. In vitro inhibition/induction studies against major human drug metabolizing enzymes/transporters suggest a low potential for perpetrator drug-drug interactions upon single-agent use of PF-07817883.