Ferroptosis mechanism and Alzheimer's disease

Regulated cell death is a genetically determined form of programmed cell death that commonly occurs during the development of living organisms.This process plays a crucial role in modulating homeostasis and is evolutionarily conserved across a diverse range of living organisms.Ferroptosis is a classic regulatory mode of cell death.Extensive studies of regulatory cell death in Alzheimer’s disease have yielded increasing evidence that fe rroptosis is closely related to the occurrence,development,and prognosis of Alzheimer’s disease.This review summarizes the molecular mechanisms of ferroptosis and recent research advances in the role of ferro ptosis in Alzheimer’s disease.Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for Alzheimer’s disease.

The “3 Genomic Numbers” Discovery: How Our Genome Single-Stranded DNA Sequence Is “Self-Designed” as a Numerical Whole

This article proves the existence of a hyper-precise global numerical meta-architecture unifying, structuring, binding and controlling the billion triplet codons constituting the sequence of single-stranded DNA of the entire human genome. Beyond the evolution and erratic mutations like transposons within the genome, it’s as if the memory of a fossil genome with multiple symmetries persists. This recalls the “intermingling” of information characterizing the fractal universe of chaos theory. The result leads to a balanced and perfect tuning between the masses of the two strands of the huge DNA molecule that constitute our genome. We show here how codon populations forming the single-stranded DNA sequences can constitute a critical approach to the understanding of junk DNA function. Then, we suggest revisiting certain methods published in our 2009 book “Codex Biogenesis”. In fact, we demonstrate here how the universal genetic code table is a powerful analytical filter to characterize single-stranded DNA sequences constituting chromosomes and genomes. We can then show that any genomic DNA sequence is featured by three numbers, which characterize it and its 64 codon populations with correlations greater than 99%. The number “1” is common to all sequences, expressing the second law of Chargaff. The other 2 numbers are related to each specific DNA sequence case characterizing life species. For example, the entire human genome is characterized by three remarkable numbers 1, 2, and Phi = 1.618 the golden ratio. Associated with each of these three numbers, we can match three axes of symmetry, then “imagine” a kind of hyperspace formed by these codon populations. Then we revisit the value (3-Phi)/2 which is probably universal and common to both the scale of quarks and atomic levels, balancing and tuning the whole human genome codon population. Finally, we demonstrate a new kind of duality between “form and substance” overlapping the whole human genome: we will show that—simultaneously with the duality between genes and junk DNA—there is a second layer of embedded hidden structure overlapping all the DNA of the whole human genome, dividing it into a second type of duality information/redundancy involving golden ratio proportions.

Liver as a new target organ in Alzheimer's disease:insight from cholesterol metabolism and its role in amyloid-beta clearance

Alzheimer's disease,the primary cause of dementia,is characterized by neuropathologies,such as amyloid plaques,synaptic and neuronal degeneration,and neurofibrillary tangles.Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs,targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment.Metabolic abnormalities are commonly observed in patients with Alzheimer's disease.The liver is the primary peripheral organ involved in amyloid-beta metabolism,playing a crucial role in the pathophysiology of Alzheimer's disease.Notably,impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease.In this review,we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism.Furthermore,we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.

Impact of apolipoprotein E isoforms on sporadic Alzheimer's disease:beyond the role of amyloid beta

The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully understood.ApoE exists as three common isoforms(ApoE2,ApoE3,and ApoE4),which differ in two amino acid residues.Traditionally,ApoE binds cholesterol and phospholipids and ApoE isoforms display diffe rent affinities for their receptors,lipids transport and distribution in the brain and periphery.The role of ApoE in the human depends on ApoE isoforms,brain regions,aging,and neural injury.APOE E4 is the strongest genetic risk factor for sporadic Alzheimer's disease,considering its role in influencing amyloid-beta metabolism.The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood,but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration,lipids metabolism,neurovascular unit,and microglial function.Consistent with the biological function of ApoE,ApoE4 isoform significantly alte red signaling pathways associated with cholesterol homeostasis,transport,and myelination.Also,the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease pathogenesis.The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE,brain function,and memory,from a molecular to a clinical level.APOE genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its outcomes.Not only in learning and memory but also in neuro psychiatric symptoms that occur in a premorbid condition.Cla rifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms,particularly suicidal ideation in Alzheimer's disease patients,may be useful for elucidating also the underlying pathophysiological process and its prognosis.Also,the effects of anti-amyloid-beta drugs,recently approved for the treatment of Alzheimer's disease,could be influenced by the APOE genotype.

Isoform-and cell-state-specific APOE homeostasis and function

Apolipoprotein E is the major lipid transporter in the brain and an important player in neuron-astrocyte metabolic coupling.It ensures the survival of neurons under stressful conditions and hyperactivity by nourishing and detoxifying them.Apolipoprotein E polymorphism,combined with environmental stresses and/or age-related alterations,influences the risk of developing late-onset Alzheimer’s disease.In this review,we discuss our current knowledge of how apolipoprotein E homeostasis,i.e.its synthesis,secretion,degradation,and lipidation,is affected in Alzheimer’s disease.

Exercise-induced modulation of miR-149-5p and MMP9 in LPS-triggered diabetic myoblast ER stress: licorice glycoside E as a potential therapeutic target

Background:This study explores the relationship between endoplasmic reticulum(ER)stress and diabetes,particularly focusing on the impact of physical exercise on ER stress mechanisms and identifying potential therapeutic drugs and targets for diabetes-related sepsis.The research also incorporates traditional physical therapy perspectives,emphasizing the genomic insights gained from exercise therapy in disease management and prevention.Methods:Gene analysis was conducted on the GSE168796 and GSE94717 datasets to identify ER stress-related genes.Gene interactions and immune cell correlations were mapped using GeneCard and STRING databases.A screening of 2,456 compounds from the TCMSP database was performed to identify potential therapeutic agents,with a focus on their docking potential.Techniques such as luciferase reporter gene assay and RNA interference were used to examine the interactions between microRNA-149-5p and MMP9.Results:The study identified 2,006 differentially expressed genes and 616 miRNAs.Key genes like MMP9,TNF-α,and IL1B were linked to an immunosuppressive state.Licorice glycoside E demonstrated high affinity for MMP9,suggesting its potential effectiveness in treating diabetes.The constructed miRNA network highlighted the regulatory roles of MMP9,IL1B,IFNG,and TNF-α.Experimental evidence confirmed the binding of microRNA-149-5p to MMP9,impacting apoptosis in diabetic cells.Conclusion:The findings highlight the regulatory role of microRNA-149-5p in managing MMP9,a crucial gene in diabetes pathophysiology.Licorice glycoside E emerges as a promising treatment option for diabetes,especially targeting MMP9 affected by ER stress.The study also underscores the significance of physical exercise in modulating ER stress pathways in diabetes management,bridging traditional physical therapy and modern scientific understanding.Our study has limitations.It focuses on the microRNA-149-5p-MMP9 network in sepsis,using cell-based methods without animal or clinical trials.Despite strong in vitro findings,in vivo studies are needed to confirm licorice glycoside E’s therapeutic potential and understand the microRNA-149-5p-MMP9 dynamics in real conditions.

Promising application of a new ulnar nerve compound muscle action potential measurement montage in amyotrophic lateral sclerosis:a prospective cross-sectional study

Previous studies have shown that ulnar nerve compound muscle action potential recorded by the conventional“belly-tendon”montage does not accurately and completely reflect the action potential of the ulnar nerve dominating the abductor digiti minimi muscle due to the effects of far-field potentials of intrinsic hand muscles.A new method of ulnar nerve compound muscle action potential measurement was developed in 2020,which adjusts the E2 electrode from the distal tendon of the abductor digitorum to the middle of the back of the proximal wrist.This new method may reduce the influence of the reference electrode and better reflect the actual ulnar nerve compound muscle action potential.In this prospective cross-sectional study,we included 64 patients with amyotrophic lateral sclerosis and 64 age-and sex-matched controls who underwent conventional and novel ulnar nerve compound muscle action potential measurement between April 2020 and May 2021 in Peking University Third Hospital.The compound muscle action potential waveforms recorded by the new montage were unimodal and more uniform than those recorded by traditional montage.In the controls,no significant difference in the compound muscle action potential waveforms was found between the traditional montage and new montage recordings.In amyotrophic lateral sclerosis patients presenting with abductor digiti minimi spontaneous activity and muscular atrophy,the amplitude of compound muscle action potential-pE2 was significantly lower than that of compound muscle action potential-dE2(P<0.01).Using the new method,damaged axons were more likely to exhibit more severe amplitude decreases than those measured with the traditional method,in particular for patients in early stage amyotrophic lateral sclerosis.In addition,the decline in compound muscle action potential amplitude measured by the new method was correlated with a decrease in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale scores.These findings suggest that the new ulnar nerve compound muscle action potential measurement montage reduces the effects of the reference electrode through altering the E2 electrode position,and that this method is more suitable for monitoring disease progression than the traditional montage.This method may be useful as a biomarker for longitudinal follow-up and clinical trials in amyotrophic lateral sclerosis.

Exploring the Latest Applications of OpenAI and ChatGPT: An In-Depth Survey

OpenAI and ChatGPT, as state-of-the-art languagemodels driven by cutting-edge artificial intelligence technology,have gained widespread adoption across diverse industries. In the realm of computer vision, these models havebeen employed for intricate tasks including object recognition, image generation, and image processing, leveragingtheir advanced capabilities to fuel transformative breakthroughs. Within the gaming industry, they have foundutility in crafting virtual characters and generating plots and dialogues, thereby enabling immersive and interactiveplayer experiences. Furthermore, these models have been harnessed in the realm of medical diagnosis, providinginvaluable insights and support to healthcare professionals in the realmof disease detection. The principal objectiveof this paper is to offer a comprehensive overview of OpenAI, OpenAI Gym, ChatGPT, DALL E, stable diffusion,the pre-trained clip model, and other pertinent models in various domains, encompassing CLIP Text-to-Image,education, medical imaging, computer vision, social influence, natural language processing, software development,coding assistance, and Chatbot, among others. Particular emphasis will be placed on comparative analysis andexamination of popular text-to-image and text-to-video models under diverse stimuli, shedding light on thecurrent research landscape, emerging trends, and existing challenges within the domains of OpenAI and ChatGPT.Through a rigorous literature review, this paper aims to deliver a professional and insightful overview of theadvancements, potentials, and limitations of these pioneering language models.

Current perspectives of viral

Viral hepatitis represents a major danger to public health,and is a globally leading cause of death.The five liver-specific viruses:Hepatitis A virus,hepatitis B virus,hepatitis C virus,hepatitis D virus,and hepatitis E virus,each have their own unique epidemiology,structural biology,transmission,endemic patterns,risk of liver complications,and response to antiviral therapies.There remain few options for treatment,in spite of the increasing prevalence of viral-hepatitiscaused liver disease.Furthermore,chronic viral hepatitis is a leading worldwide cause of both liver-related morbidity and mortality,even though effective treatments are available that could reduce or prevent most patients’complications.In 2016,the World Health Organization released its plan to eliminate viral hepatitis as a public health threat by the year 2030,along with a discussion of current gaps and prospects for both regional and global eradication of viral hepatitis.Today,treatment is sufficiently able to prevent the disease from reaching advanced phases.However,future therapies must be extremely safe,and should ideally limit the period of treatment necessary.A better understanding of pathogenesis will prove beneficial in the development of potential treatment strategies targeting infections by viral hepatitis.This review aims to summarize the current state of knowledge on each type of viral hepatitis,together with major innovations.

Withaferin A inhibits ferroptosis and protects against intracerebral hemorrhage

Recent studies have indicated that suppressing oxidative stress and ferroptosis can considerably improve the prognosis of intracerebral hemorrhage(ICH).Withaferin A(WFA),a natural compound,exhibits a positive effect on a number of neurological diseases.However,the effects of WFA on oxidative stress and ferroptosis-mediated signaling pathways to ICH remain unknown.In this study,we investigated the neuroprotective effects and underlying mechanism for WFA in the regulation of ICH-induced oxidative stress and ferroptosis.We established a mouse model of ICH by injection of autologous tail artery blood into the caudate nucleus and an in vitro cell model of hemin-induced ICH.WFA was injected intracerebroventricularly at 0.1,1 or 5μg/kg once daily for 7 days,starting immediately after ICH operation.WFA markedly reduced brain tissue injury and iron deposition and improved neurological function in a dose-dependent manner 7 days after cerebral hemorrhage.Through in vitro experiments,cell viability test showed that WFA protected SH-SY5Y neuronal cells against hemin-induced cell injury.Enzyme-linked immunosorbent assays in vitro and in vivo showed that WFA markedly decreased the level of malondialdehyde,an oxidative stress marker,and increased the activities of anti-oxidative stress markers superoxide dismutase and glutathione peroxidase after ICH.Western blot assay,quantitative polymerase chain reaction and immunofluorescence results demonstrated that WFA activated the nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)signaling axis,promoted translocation of Nrf2 from the cytoplasm to nucleus,and increased HO-1 expression.Silencing Nrf2 with siRNA completely reversed HO-1 expression,oxidative stress and protective effects of WFA.Furthermore,WFA reduced hemin-induced ferroptosis.However,after treatment with an HO-1 inhibitor,the neuroprotective effects of WFA against hemin-induced ferroptosis were weakened.MTT test results showed that WFA combined with ferrostatin-1 reduced hemin-induced SH-SY5Y neuronal cell injury.Our findings reveal that WFA treatment alleviated ICH injury-induced ferroptosis and oxidative stress through activating the Nrf2/HO-1 pathway,which may highlight a potential role of WFA for the treatment of ICH.

Protective actions of salvianolic acid A on hepatocyte injured by peroxidation in vitro

INTRODUCTION Salvianolic radix,one of the most commonly usedtraditional Chinese herbs,was widely studied aboutits actions against liver injury and fibrosis,and wasone of the focuses of recent research.Salvianolic acid-A(SA-A)was an aqueous solublecomponent of Salvianolic radix.In our

A Fractal Rindler-Regge Triangulation in the Hyperbolic Plane and Cosmic de Sitter Accelerated Expansion

The well known finite elements Regge calculus is transformed to a triangulation in the hyperbolic plane using fractal Rindler wedges as tiling elements. The final result is an expanding de Sitter hyperbolic, i.e. Gauss-Bolyai-Lobachevsky universe with dark energy and ordinary energy densities in full agreement with cosmic observations and measurements. In the course of obtaining this vital result, the work addresses fundamental points connected to a host of subjects, namely Hardy’s quantum entanglement, an extension of Turing’s machine to a transfinite version, the phenomenon of measure concentration in the context of Banach-like spaces with high dimensionality as well as the pioneering work on the relation between quantum entanglement and computational efficiency.

Rational and Continuous Measurement of the Emotional Decision Making in Visual Recognition of Facial Emotional Expressions with M.A.R.I.E.: First Half

Context: The advent of Artificial Intelligence (AI) requires modeling prior to its implementation in algorithms for most human skills. This observation requires us to have a detailed and precise understanding of the interfaces of verbal and emotional communications. The progress of AI is significant on the verbal level but modest in terms of the recognition of facial emotions even if this functionality is one of the oldest in humans and is omnipresent in our daily lives. Dysfunction in the ability for facial emotional expressions is present in many brain pathologies encountered by psychiatrists, neurologists, psychotherapists, mental health professionals including social workers. It cannot be objectively verified and measured due to a lack of reliable tools that are valid and consistently sensitive. Indeed, the articles in the scientific literature dealing with Visual-Facial-Emotions-Recognition (ViFaEmRe), suffer from the absence of 1) consensual and rational tools for continuous quantified measurement, 2) operational concepts. We have invented a software that can use computer-morphing attempting to respond to these two obstacles. It is identified as the Method of Analysis and Research of the Integration of Emotions (M.A.R.I.E.). Our primary goal is to use M.A.R.I.E. to understand the physiology of ViFaEmRe in normal healthy subjects by standardizing the measurements. Then, it will allow us to focus on subjects manifesting abnormalities in this ability. Our second goal is to make our contribution to the progress of AI hoping to add the dimension of recognition of facial emotional expressions. Objective: To study: 1) categorical vs dimensional aspects of recognition of ViFaEmRe, 2) universality vs idiosyncrasy, 3) immediate vs ambivalent Emotional-Decision-Making, 4) the Emotional-Fingerprint of a face and 5) creation of population references data. Methods: With M.A.R.I.E. enable a rational quantified measurement of Emotional-Visual-Acuity (EVA) of 1) a) an individual observer, b) in a population aged 20 to 70 years old, 2) measure the range and intensity of expressed emotions by 3 Face-Tests, 3) quantify the performance of a sample of 204 observers with hyper normal measures of cognition, “thymia,” (ibid. defined elsewhere) and low levels of anxiety 4) analysis of the 6 primary emotions. Results: We have individualized the following continuous parameters: 1) “Emotional-Visual-Acuity”, 2) “Visual-Emotional-Feeling”, 3) “Emotional-Quotient”, 4) “Emotional-Deci-sion-Making”, 5) “Emotional-Decision-Making Graph” or “Individual-Gun-Trigger”6) “Emotional-Fingerprint” or “Key-graph”, 7) “Emotional-Finger-print-Graph”, 8) detecting “misunderstanding” and 9) detecting “error”. This allowed us a taxonomy with coding of the face-emotion pair. Each face has specific measurements and graphics. The EVA improves from ages of 20 to 55 years, then decreases. It does not depend on the sex of the observer, nor the face studied. In addition, 1% of people endowed with normal intelligence do not recognize emotions. The categorical dimension is a variable for everyone. The range and intensity of ViFaEmRe is idiosyncratic and not universally uniform. The recognition of emotions is purely categorical for a single individual. It is dimensional for a population sample. Conclusions: Firstly, M.A.R.I.E. has made possible to bring out new concepts and new continuous measurements variables. The comparison between healthy and abnormal individuals makes it possible to take into consideration the significance of this line of study. From now on, these new functional parameters will allow us to identify and name “emotional” disorders or illnesses which can give additional dimension to behavioral disorders in all pathologies that affect the brain. Secondly, the ViFaEmRe is idiosyncratic, categorical, and a function of the identity of the observer and of the observed face. These findings stack up against Artificial Intelligence, which cannot have a globalist or regionalist algorithm that can be programmed into a robot, nor can AI compete with human abilities and judgment in this domain. *Here “Emotional disorders” refers to disorders of emotional expressions and recognition.

Rational and Continuous Measurement of Emotional-Fingerprint, Emotional-Quotient and Categorical vs Proportional Recognition of Facial Emotions with M.A.R.I.E., Second Half

Context: The advent of Artificial Intelligence (AI) requires modeling prior to its implementation in algorithms for most human skills. This observation requires us to have a detailed and precise understanding of the interfaces of verbal and emotional communications. The progress of AI is significant on the verbal level but modest in terms of the recognition of facial emotions even if this functionality is one of the oldest in humans and is omnipresent in our daily lives. Dysfunction in the ability for facial emotional expressions is present in many brain pathologies encountered by psychiatrists, neurologists, psychotherapists, mental health professionals including social workers. It cannot be objectively verified and measured due to a lack of reliable tools that are valid and consistently sensitive. Indeed, the articles in the scientific literature dealing with Visual-Facial-Emotions-Recognition (ViFaEmRe), suffer from the absence of 1) consensual and rational tools for continuous quantified measurement, 2) operational concepts. We have invented a software that can use computer-morphing attempting to respond to these two obstacles. It is identified as the Method of Analysis and Research of the Integration of Emotions (M.A.R.I.E.). Our primary goal is to use M.A.R.I.E. to understand the physiology of ViFaEmRe in normal healthy subjects by standardizing the measurements. Then, it will allow us to focus on subjects manifesting abnormalities in this ability. Our second goal is to make our contribution to the progress of AI hoping to add the dimension of recognition of facial emotional expressions. Objective: To study: 1) categorical vs dimensional aspects of recognition of ViFaEmRe, 2) universality vs idiosyncrasy, 3) immediate vs ambivalent Emotional-Decision-Making, 4) the Emotional-Fingerprint of a face and 5) creation of population references data. Methods: M.A.R.I.E. enables the rational, quantified measurement of Emotional Visual Acuity (EVA) in an individual observer and a population aged 20 to 70 years. Meanwhile, it can measure the range and intensity of expressed emotions through three Face- Tests, quantify the performance of a sample of 204 observers with hypernormal measures of cognition, “thymia” (defined elsewhere), and low levels of anxiety, and perform analysis of the six primary emotions. Results: We have individualized the following continuous parameters: 1) “Emotional-Visual- Acuity”, 2) “Visual-Emotional-Feeling”, 3) “Emotional-Quotient”, 4) “Emotional-Decision-Making”, 5) “Emotional-Decision-Making Graph” or “Individual-Gun-Trigger”, 6) “Emotional-Fingerprint” or “Key-graph”, 7) “Emotional-Fingerprint-Graph”, 8) detecting “misunderstanding” and 9) detecting “error”. This allowed us a taxonomy with coding of the face-emotion pair. Each face has specific measurements and graphics. The EVA improves from ages of 20 to 55 years, then decreases. It does not depend on the sex of the observer, nor the face studied. In addition, 1% of people endowed with normal intelligence do not recognize emotions. The categorical dimension is a variable for everyone. The range and intensity of ViFaEmRe is idiosyncratic and not universally uniform. The recognition of emotions is purely categorical for a single individual. It is dimensional for a population sample. Conclusions: Firstly, M.A.R.I.E. has made possible to bring out new concepts and new continuous measurements variables. The comparison between healthy and abnormal individuals makes it possible to take into consideration the significance of this line of study. From now on, these new functional parameters will allow us to identify and name “emotional” disorders or illnesses which can give additional dimension to behavioral disorders in all pathologies that affect the brain. Secondly, the ViFaEmRe is idiosyncratic, categorical, and a function of the identity of the observer and of the observed face. These findings stack up against Artificial Intelligence, which cannot have a globalist or regionalist algorithm that can be programmed into a robot, nor can AI compete with human abilities and judgment in this domain. *Here “Emotional disorders” refers to disorders of emotional expressions and recognition.

Animal models of hepatitis E infection: Advances and challenges

Hepatitis E virus(HEV)is one of the leading causes of acute viral hepatitis worldwide.Although most of HEV infections are asymptomatic,some patients will develop the symptoms,especially pregnant women,the elderly,and patients with preexisting liver diseases,who often experience anorexia,nausea,vom-iting,malaise,abdominal pain,and jaundice.HEV infection may become chronic in immunosuppressed individuals.In addition,HEV infection can also cause several extrahepatic manifestations.HEV exists in a wide range of hosts in nature and can be transmitted across species.Hence,animals susceptible to HEV can be used as models.The establishment of animal models is of great significance for studying HEV transmission,clinical symptoms,extrahepatic manifestations,and therapeutic strategies,which will help us understand the pathogenesis,prevention,and treatment of hepatitis E.This review summarized the animal models of HEV,including pigs,monkeys,rabbits,mice,rats,and other animals.For each animal species,we provided a concise summary of the HEV genotypes that they can be infected with,the cross-species transmission pathways,as well as their role in studying extrahepatic manifestations,prevention,and treatment of HEV infection.The advantages and disadvantages of these animal models were also emphasized.This review offers new perspectives to enhance the current understanding of the research landscape surrounding HEV animal models.

The role of antioxidants and pro-oxidants in colon cancer

This review focuses on the roles antioxidants and prooxidants in colorectal cancer(CRC).Considerable evidence suggests that environmental factors play key roles in the incidence of sporadic CRC.If pro-oxidant factors play an etiological role in CRC it is reasonable to expect causal interconnections between the wellcharacterized risk factors for CRC,oxidative stress and genotoxicity.Cigarette smoking,a high dietary consumption of n-6 polyunsaturated fatty acids and alcohol intake are all associated with increased CRC risk.These risk factors are all pro-oxidant stressors and their connections to oxidative stress,the intestinal microbiome,intestinal microfold cells,cyclooxygenase-2 and CRCare detailed in this review.While a strong case can be made for pro-oxidant stressors in causing CRC,the role of food antioxidants in preventing CRC is less certain.It is clear that not every micronutrient with antioxidant activity can prevent CRC.It is plausible,however,that the optimal food antioxidants for preventing CRC have not yet been critically evaluated.Increasing evidence suggests that RRR-gamma-tocopherol(the primary dietary form of vitamin E)or other"non-alpha-tocopherol"forms of vitamin E(e.g.,tocotrienols)might be effective.Aspirin is an antioxidant and its consumption is linked to a decreased risk of CRC.

Genome-wide association mapping and genomic prediction of stalk rot in two mid-altitude tropical maize populations

Maize stalk rot reduces grain yield and quality.Information about the genetics of resistance to maize stalk rot could help breeders design effective breeding strategies for the trait.Genomic prediction may be a more effective breeding strategy for stalk-rot resistance than marker-assisted selection.We performed a genome-wide association study(GWAS)and genomic prediction of resistance in testcross hybrids of 677 inbred lines from the Tuxpe?o and non-Tuxpe?o heterotic pools grown in three environments and genotyped with 200,681 single-nucleotide polymorphisms(SNPs).Eighteen SNPs associated with stalk rot shared genomic regions with gene families previously associated with plant biotic and abiotic responses.More favorable SNP haplotypes traced to tropical than to temperate progenitors of the inbred lines.Incorporating genotype-by-environment(G×E)interaction increased genomic prediction accuracy.

Subclinical hepatitis E virus genotype 1 infection:The concept of“dynamic human reservoir”

Hepatitis E virus(HEV)is hyperendemic in South Asia and Africa accounting for half of total Global HEV burden.There are eight genotypes of HEV.Among them,the four common ones known to infect humans,genotypes 1 and 2 are prevalent in the developing world and genotypes 3 and 4 are causing challenge in the industrialized world.Asymptomatic HEV viremia in the general population,especially among blood donors,has been reported in the literature worldwide.The clinical implications related to this asymptomatic viremia are unclear and need further exploration.Detection of viremia due to HEV genotype 1 infection,apparently among healthy blood donors is also reported without much knowledge about its infection rate.Similarly,while HEV genotype 3 is known to be transmitted via blood transfusion in humans and has been subjected to screening in many European nations,instances of transmission have also been documented albeit without significant clinical consequences.Epidemiology of HEV genotype 1 in endemic areas often show waxing and waning pattern.Occasional sporadic occurrence of HEV infection interrupted by outbreaks have been frequently seen.In absence of known animal reservoir,where HEV exists in between outbreak is a mystery that needs further exploration.However,occurrence of asymptomatic HEV viremia due to HEV genotype 1 during epidemiologically quiescent period may explain that this phenomenon may act as a dynamic reservoir.Since HEV genotype 1 infection cannot cause chronicity,subclinical transient infection and transmission of virus might be the reason it sustains in interepidemic period.This might be the similar phenomenon with SARS COVID-19 corona virus infection which is circulating worldwide in distinct phases with peaks and plateaus despite vaccination against it.In view of existing evidence,we propose the concept of“Dynamic Human Reservoir.”Quiescent subclinical infection of HEV without any clinical consequences and subsequent transmission may contribute to the existence of the virus in a community.The potential for transmitting HEV infection by asymptomatic HEV infected individuals by fecal shedding of virus has not been reported in literature.This missing link may be a key to Pandora's box in understanding epidemiology of HEV infection in genotype 1 predominant region.

Realm of hepatitis E:Challenges and opportunities

Hepatitis E virus(HEV),responsible for widespread viral hepatitis,infects approximately 2.3 billion individuals globally,with a significant mortality burden in Asia.The virus,primarily transmitted through contaminated water and undercooked meat,is often underdiagnosed,particularly in immunocompromised patients.Current HEV treatments,while effective,are limited by adverse effects,necessitating research into safer alternatives.Moreover,HEV’s extrahepatic manifestations,impacting the nervous and renal systems,remain poorly understood.This study underscores the imperative for enhanced HEV research,improved diagnostic methods,and more effective treatments,coupled with increased public health awareness and preventive strategies.

MMAE-loaded PLGA nanomedicine with improved biosafety to achieve efficient antitumor treatment

Monomethyl auristatin E(MMAE)is a derivative of the marine peptide Dolastatin 10,which has therapeutic effects against various cancers according to its antimitotic activity in multiple clinical trials.The antibody drug conjugate(ADC)of MMAE is currently used in clinical practice.However,the safety issues of MMAE-based ADC,such as high drug toxicity and poor bioavailability,still exist when using it for anticancer therapy.A sustained release of drug delivery approach should be used to reduce toxicity and achieve sufficient anticancer effects.Herein,PLGA-b-PEG 2000 with excellent biocompatibility and slow degradation ability was adopted to construct MMAE-loaded nanoparticles for safe and effective chemotherapy.The sustained release effect and the immunogenic cell death(ICD)effect of PLGA-MMAE nanoparticles were assessed by in vitro experiments.The PLGA-MMAE nanoparticles effectively accumulated in the tumor through the enhanced permeability and retention(EPR)effect,inducing cell apoptosis and causing a certain degree of immune response.The sustained drug release of PLGA-MMAE improved the bioavailability and effectively reduced the toxicity and development of the tumor compared to the effect of free MMAE or ADC.Overall,this study provides a safe and effective chemotherapeutic approach,as well as a simple and effective synthetic process for MMAE-based nanoparticles,improving their therapeutic efficacy and safety.