Genetic and epigenetic targets of natural dietary compounds as anti-Alzheimer's agents

Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia that principally affects older adults.Pathogenic factors,such as oxidative stress,an increase in acetylcholinesterase activity,mitochondrial dysfunction,genotoxicity,and neuroinflammation are present in this syndrome,which leads to neurodegeneration.Neurodegenerative pathologies such as Alzheimer’s disease are considered late-onset diseases caused by the complex combination of genetic,epigenetic,and environmental factors.There are two main types of Alzheimer’s disease,known as familial Alzheimer’s disease(onset<65 years)and late-onset or sporadic Alzheimer’s disease(onset≥65 years).Patients with familial Alzheimer’s disease inherit the disease due to rare mutations on the amyloid precursor protein(APP),presenilin 1 and 2(PSEN1 and PSEN2)genes in an autosomaldominantly fashion with closely 100%penetrance.In contrast,a different picture seems to emerge for sporadic Alzheimer’s disease,which exhibits numerous non-Mendelian anomalies suggesting an epigenetic component in its etiology.Importantly,the fundamental pathophysiological mechanisms driving Alzheimer’s disease are interfaced with epigenetic dysregulation.However,the dynamic nature of epigenetics seems to open up new avenues and hope in regenerative neurogenesis to improve brain repair in Alzheimer’s disease or following injury or stroke in humans.In recent years,there has been an increase in interest in using natural products for the treatment of neurodegenerative illnesses such as Alzheimer’s disease.Through epigenetic mechanisms,such as DNA methylation,non-coding RNAs,histone modification,and chromatin conformation regulation,natural compounds appear to exert neuroprotective effects.While we do not purport to cover every in this work,we do attempt to illustrate how various phytochemical compounds regulate the epigenetic effects of a few Alzheimer’s disease-related genes.

Natural Numbers and the Strong Goldbach Conjecture

This study introduces the representation of natural number sets as row vectors and pretends to offer a new perspective on the strong Goldbach conjecture. The natural numbers are restructured and expanded with the inclusion of the zero element as the source of a strong Goldbach conjecture reformulation. A prime Boolean vector is defined, pinpointing the positions of prime numbers within the odd number sequence. The natural unit primality is discussed in this context and transformed into a source of quantum-like indetermination. This approach allows for rephrasing the strong Goldbach conjecture, framed within a Boolean scalar product between the prime Boolean vector and its reverse. Throughout the discussion, other intriguing topics emerge and are thoroughly analyzed. A final description of two empirical algorithms is provided to prove the strong Goldbach conjecture.

The “Dead Universe” Theory: Natural Separation of Galaxies Driven by the Remnants of a Supermassive Dead Universe

This article explores the dead universe theory as a novel interpretation for the origin and evolution of the universe, suggesting that our cosmos may have originated from the remnants of a preceding universe. This perspective challenges the conventional Big Bang theory, particularly concerning dark matter, the expansion of the universe, and the interpretation of phenomena such as gravitational waves.

基于TDLAS的天然气泄漏范围重构方法

可调谐半导体激光光谱(TDLAS)技术因其灵出色的灵敏度、精度和抗干扰性的特性,现已被广泛应用于场站天然气泄漏的监测工作。为克服单台TDLAS激光遥测仪无法获得泄漏气体扩散影响范围的局限性,本文提出了一种基于多台TDLAS遥测仪协同的智能监测方法,通过在不同斜平面内对泄漏气团进行扫查,依据Brianchon定理获得不同斜平面内气体泄漏的外轮廓方程,重构天然气的三维空间泄漏影响区域,实时开展监测与预警。

Proximity to corridors benefits bird communities in vegetated interrow vineyards in Mendoza, Argentina

Management under ecological schemes and increasing habitat heterogeneity,are essential for enhancing biodiversity in vineyards.Birds provide several contributions to agriculture,for example pest control,recreation and enhancing human mental health,and have intrinsic value.Birds are also ideal model organisms because they are easy to survey,and species respond differently to agricultural land use at different scales.Vegetated borders of crops are key for many species of birds,and distance to the border have been found to be an important factor in vineyard-dominated agroecosystems.We evaluate if there are differences in the bird assemblage,between the interior compared to borders within vineyards,using a hierarchical community occupancy model.We hypoth-esized that occupancy of birds is greater in environments with greater heterogeneity,which in this study was considered to be contributed by the proximity to vegetated corridors.We expected that vineyard borders close to corridors will have higher bird occupancy than the center of the vineyard.The research was conducted in three vineyards with biodiversity-friendly management practices,in Gualtallary,Mendoza,Argentina.Bird surveys were conducted over three breeding seasons from 2018 to 2020.Occupancy and richness of the bird community was more closely associated with the borders adjacent to the corridors than with the interior of the vineyards,as we initially predicted,although the assemblage of birds did not differ much.More than 75%of the registered species consume exclusively or partially invertebrates.Biodiversity-friendly management and ecological schemes,together with vegetated corridors provide multiple benefits for biodiversity conservation.These ap-proaches not only minimize the use of agrochemicals but also prioritize soil cover with spontaneous vegetation,which supports a diverse community of insectivorous bird species,potentially contributing to pest control.

Digital Disparities:How Artificial Intelligence Can Facilitate Anti-Black Racism in the U.S.Healthcare Sector

This paper delves into the intricate interplay between artificial intelligence(AI)systems and the perpetuation of Anti-Black racism within the United States medical industry.Despite the promising potential of AI to enhance healthcare outcomes and reduce disparities,there is a growing concern that these technologies may inadvertently/advertently exacerbate existing racial inequalities.Focusing specifically on the experiences of Black patients,this research investigates how the following AI components:medical algorithms,machine learning,and natural learning processes are contributing to the unequal distribution of medical resources,diagnosis,and health care treatment of those classified as Black.Furthermore,this review employs a multidisciplinary approach,combining insights from computer science,medical ethics,and social justice theory to analyze the mechanisms through which AI systems may encode and reinforce racial biases.By dissecting the three primary components of AI,this paper aims to present a clear understanding of how these technologies work,how they intersect,and how they may inherently perpetuate harmful stereotypes resulting in negligent outcomes for Black patients.Furthermore,this paper explores the ethical implications of deploying AI in healthcare settings and calls for increased transparency,accountability,and diversity in the development and implementation of these technologies.Finally,it is important that I prefer the following paper with a clear and concise definition of what I refer to as Anti-Black racism throughout the text.Therefore,I assert the following:Anti-Black racism refers to prejudice,discrimination,or antagonism directed against individuals or communities of African descent based on their race.It involves the belief in the inherent superiority of one race over another and the systemic and institutional practices that perpetuate inequality and disadvantage for Black people.Furthermore,I proclaim that this form of racism can be manifested in various ways,such as unequal access to opportunities,resources,education,employment,and fair treatment within social,economic,and political systems.It is also pertinent to acknowledge that Anti-Black racism is deeply rooted in historical and societal structures throughout the U.S.borders and beyond,leading to systemic disadvantages and disparities that impact the well-being and life chances of Black individuals and communities.Addressing Anti-Black racism involves recognizing and challenging both individual attitudes and systemic structures that contribute to discrimination and inequality.Efforts to combat Anti-Black racism include promoting awareness,education,advocacy for policy changes,and fostering a culture of inclusivity and equality.

Effects of a Cocktail Supplement of Ginkgo Biloba and Acai Extract on Cognitive Symptoms of Parkinson’s Disease

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, including cognitive impairment. Current treatments often involve synthetic drugs with significant side effects and potential for dependency. This study investigates the effects of a natural supplement combination of Ginkgo Biloba and Acai Extract on cognitive symptoms in a 77-year-old male with PD. The participant underwent a three-month supplementation regimen, with cognitive function assessed using the Montreal Cognitive Assessment (MoCA) test before and after the intervention. The results indicated an improvement in cognitive scores, suggesting that the combination of Ginkgo Biloba and Acai Extract may offer a promising alternative or adjunct to conventional PD treatments. This study highlights the potential of natural supplements in managing PD symptoms and calls for further research with larger sample sizes to confirm these findings. Human data was performed in accordance with the Declaration of Helsinki by the Roxbury District IRB Board (IRB Number: IRB00011767).

Whole Perfect Vectors and Fermat’s Last Theorem

A naïve discussion of Fermat’s last theorem conundrum is described. The present theorem’s proof is grounded on the well-known properties of sums of powers of the sine and cosine functions, the Minkowski norm definition, and some vector-specific structures.

Analysis of the supply-demand status of China's natural gas to 2020

The reserves, distribution, production and utilization of natural gas resources in China are introduced in this paper which leads a point of view that China＇s natural gas resources are relatively rich while distributed unevenly. The future production and consumption of China＇s natural gas are predicted using the Generalized Weng model and the Gray prediction model. The prediction suggests that with the increasing gas consumption China＇s natural gas production will not meet demand after 2010. In order to ease the supply-demand gap and realize rational development and utilization of China＇s natural gas resources, this paper puts forward some measures, such as using advanced technologies for natural gas development, establishing a long-distance pipeline network to rationalize the availability of natural gas across China and importing foreign natural gas and liquid natural gas （LNG）.

Natural history and long-term clinical course of Crohn's disease

Crohn&#x02019;s disease is a chronic inflammatory disease process involving different sites in the gastrointestinal tract. Occasionally, so-called metastatic disease occurs in extra-intestinal sites. Granulomatous inflammation may be detected in endoscopic biopsies or resected tissues. Genetic, epigenetic and environmental factors appear to play a role. Multiple susceptibility genes have been described in both familial and non-familial forms while the disease is phenotypically heterogeneous with a female predominance. The disorder occurs over a broad age spectrum, from early childhood to late adulthood. More than 80% are diagnosed before age 40 years usually with terminal ileal and colonic involvement. Pediatric-onset disease is more severe and more extensive, usually with a higher chance of upper gastrointestinal tract disease, compared to adult-onset disease. Long-term studies have shown that the disorder may evolve with time into more complex disease with stricture formation and penetrating disease complications (i.e., fistula, abscess). Although prolonged remission may occur, discrete periods of symptomatic disease may re-appear over many decades suggesting recurrence or re-activation of this inflammatory process. Eventual development of a cure will likely depend on identification of an etiologic cause and a fundamental understanding of its pathogenesis. Until now, treatment has focused on removing risk factors, particularly cigarette smoking, and improving symptoms. In clinical trials, clinical remission is largely defined as improved numerical and endoscopic indices for &#x0201c;mucosal healing&#x0201d;. &#x0201c;Deep remission&#x0201d; is a conceptual, more &#x0201c;extended&#x0201d; goal that may or may not alter the long-term natural history of the disease in selected patients, albeit at a significant risk for treatment complications, including serious and unusual opportunistic infections.

Exploring the efficacy of natural products in alleviating Alzheimer’s disease

Alzheimer’s disease(hereafter AD) is a progressive neurodegenerative disorder that affects the central nervous system. There are multiple factors that cause AD, viz., accumulation of extracellular Amyloid-beta 42 plaques, intracellular hyper-phosphorylated Tau tangles, generation of reactive oxygen species due to mitochondrial dysfunction and genetic mutations. The plaques and tau tangles trigger aberrant signaling, which eventually cause cell death of the neurons. As a result, there is shrinkage of brain, cognitive defects, behavioral and psychological problems. To date, there is no direct cure for AD. Thus, scientists have been testing various strategies like screening for the small inhibitor molecule library or natural products that may block or prevent onset of AD. Historically, natural products have been used in many cultures for the treatment of various diseases. The research on natural products have gained importance as the active compounds extracted from them have medicinal values with reduced side effects, and they are bioavailable. The natural products may target the proteins or members of signaling pathways that get altered in specific diseases. Many natural products are being tested in various animal model systems for their role as a potential therapeutic target for AD, and to address questions about how these natural products can rescue AD or other neurodegenerative disorders. Some of these products are in clinical trials and results are promising because of their neuroprotective, anti-inflammatory, antioxidant, anti-amyloidogenic, anticholinesterase activities and easy availability. This review summarizes the use of animal model systems to identify natural products, which may serve as potential therapeutic targets for AD.

Natural polyphenols effects on protein aggregates in Alzheimer＇s and Parkinson＇s prion-like diseases

Alzheimer＇s and Parkinson＇s diseases are the most common neurodegenerative diseases. They are characterized by protein aggregates and so can be considered as prion-like disease. The major components of these deposits are amyloid peptide and tau for Alzheimer＇s disease, α-synuclein and synphilin-1 for Parkinson＇s disease. Drugs currently proposed to treat these pathologies do not prevent neurodegenerative processes and are mainly symptomatic therapies. Molecules inducing inhibition of aggregation or disaggregation of these proteins could have beneficial effects, especially if they have other beneficial effects for these diseases. Thus, several natural polyphenols, which have antioxidative, anti-inflammatory and neuroprotective properties, have been largely studied, for their effects on protein aggregates found in these diseases, notably in vitro. In this article, we propose to review the significant papers concerning the role of polyphenols on aggregation and disaggregation of amyloid peptide, tau, α-synuclein, synphilin-1, suggesting that these compounds could be useful in the treatments in Alzheimer＇s and Parkinson＇s diseases.

Interventions of natural and synthetic agents in inflammatory bowel disease, modulation of nitric oxide pathways

Inflammatory bowel disease(IBD)refers to a group of disorders characterized by chronic inflammation of the gastrointestinal(GI)tract.The elevated levels of nitric oxide(NO)in serum and affected tissues;mainly synthesized by the inducible nitric oxide synthase(iNOS)enzyme;can exacerbate GI inflammation and is one of the major biomarkers of GI inflammation.Various natural and synthetic agents are able to ameliorate GI inflammation and decrease iNOS expression to the extent comparable with some IBD drugs.Thereby,the purpose of this study was to gather a list of natural or synthetic mediators capable of modulating IBD through the NO pathway.Electronic databases including Google Scholar and PubMed were searched from 1980 to May 2018.We found that polyphenols and particularly flavonoids are able to markedly attenuate NO production and iNOS expression through the nuclear factorκB(NF-κB)and JAK/STAT signaling pathways.Prebiotics and probiotics can also alter the GI microbiota and reduce NO expression in IBD models through a broad array of mechanisms.A number of synthetic molecules have been found to suppress NO expression either dependent on the NF-κB signaling pathway(i.e.,dexamethasone,pioglitazone,tropisetron)or independent from this pathway(i.e.,nicotine,prednisolone,celecoxib,β-adrenoceptor antagonists).Co-administration of natural and synthetic agents can affect the tissue level of NO and may improve IBD symptoms mainly by modulating the Toll like receptor-4 and NF-κB signaling pathways.

The Effects of Natural Capital Protection on Pastoralist's Livelihood and Management Implication in the Source Region of the Yellow River, China

The interaction among different livelihood capitals is a key to generate a deeper understanding of the livelihood sustainability.In this paper,we use net income per capita(economic capital),meat and milk production per capita(physical capital),and areas of fenced pasture,livestock shelter,grassland rodent control and planted grassland(physical capital) as proxy indicators of livelihood promotion,livelihood provision,and livelihood protection respectively.By developing a correlation model between pastoralists' livelihood protection and improvement,we found that(1) there is a statistically significant correlation between the pastoralists' livelihood protection and promotion;(2) based on the maximum effect of pastoralists' livelihood promotion and provision,there is a benchmark in the effect of the intervention intensity of livelihood capital(grassland resource protection) on livelihood improvement;(3) on basis of two indicators,i.e.net income per capita and meat production per capita,the reasonable scales of fenced pasture,livestock shelter and planted grassland are less than 843,860 and 46 thousand hectares(hm2) per year respectively.With the marginal effect of livelihood protection,moderately decreased areas of fenced pasture and planted grassland,and increased area of livestock shelter is a critical to ensure pastoralist's livelihood sustainability.

Neuroglobin and neuroprotection:the role of natural and synthetic compounds in neuroglobin pharmacological induction

Neuroglobin(Ngb)is a 17 kDa monomeric hexa-coordinated heme protein belonging to the globin family.Ngb is mainly expressed in neurons of the central and peripheral nervous system,although moderate levels of Ngb have been detected in non-nervous tissues.In the past decade,Ngb has been studied for its neuroprotective role in a large number of neurological disorders such as Alzheimer’s disease,Huntington’s disease,brain ischemia and hypoxia.This review discusses and summarizes the natural compounds and the small synthetic molecules capable of modulating Ngb expression that exhibits a protective role against various neurodegenerative diseases.

Long-term natural history of Crohn’s disease

Crohn’s disease is a chronic inflammatory granulomatous process that usually involves different sites in the intestinal tract. Genetic and environmental factors are thought to play a role in its etiology and pathogenesis. The disorder has a heterogeneous clinical expression and data from tertiary care settings have documented its female predominance, occasional familial nature, and high rate of stricture formation and penetrating disease. It may appear from early childhood to late adulthood, although over 80% are currently diagnosed before age 40 years, usually with terminal ileal and colonic involvement. Several studies have now shown differences in phenotypic clinical expression depending on the initial age at diagnosis, with pediatric-onset disease being more severe and more extensive with more involvement of the upper gastrointestinal tract compared to adult-onset disease. In addition, long- term studies from these tertiary care settings have documented that the disorder may evolve with time into a more complex disease with stricture formation and penetrating disease complications (i.e. fistula and abscess). Although prolonged remission with no evidence of inflammatory disease may occur, discrete periods of symptomatic and active granulomatous inflammatory disease may re-appear over many decades. Long-term studies on the natural history have also suggested that discrete events (or agents) may precipitate this granulomatous inflammatory process.

NANOMECHANICAL MAPPING OF CARBON BLACK REINFORCED NATURAL RUBBER BY ATOMIC FORCE MICROSCOPY

Atomic force microscopy （AFM） has the advantage of obtaining mechanical properties as well as topographic information at the same time. By analyzing force-distance curves measured over two-dimensional area using Hertzian contact mechanics, Young＇s modulus mapping was obtained with nanometer-scale resolution. Furthermore, the sample deformation by the force exerted was also estimated from the force-distance curve analyses. We could thus reconstruct a real topographic image by incorporating apparent topographic image with deformation image. We applied this method to carbon black reinforced natural rubber to obtain Young＇s modulus distribution image together with reconstructed real topographic image. Then we were able to recognize three regions; rubber matrix, carbon black （or bound rubber） and intermediate regions. Though the existence of these regions had been investigated by pulsed nuclear magnetic resonance, this paper would be the first to report on the quantitative evaluation of the interfacial region in real space.

Crucial steps in the natural history of inflammatory bowel disease

Inflammatory bowel diseases(IBD),including ulcerative colitis(UC) and Crohn's disease(CD),are chronic,progressive and disabling disorders.Over the last few decades,new therapeutic approaches have been introduced which have led not only to a reduction in the mortality rate but also offered the possibility of a favorable modification in the natural history of IBD.The identification of clinical,genetic and serological prognostic factors has permitted a better stratification of the disease,thus allowing the opportunity to indicate the most appropriate therapy.Early treatment with immunosuppressive drugs and biologics has offered the opportunity to change,at least in the short term,the course of the disease by reducing,in a subset of patients with IBD,hospitalization and the need for surgery.In this review,the crucial steps in the natural history of both UC and CD will be discussed,as well as the factors that may change their clinical course.The methodological requirements for high quality studies on the course and prognosis of IBD,the true impact of environmental and dietary factors on the clinical course of IBD,the clinical,serological and genetic predictors of the IBD course(in particular,which of these are rel-evant and appropriate for use in clinical practice),the impact of the various forms of medical treatment on the IBD complication rate,the role of surgery for IBD in the biologic era,the true magnitude of risk of colorectal cancer associated with IBD,as well as the mortality rate related to IBD will be stressed;all topics that are extensively discussed in separate reviews included in this issue of World Journal of Gastroenterology.

Inflammatory bowel disease course in Crohn's disease:Is the natural history changing?

Crohn&#x02019;s disease (CD) is a multifactorial potentially debilitating disease. It has a variable disease course, but the majority of patients eventually develop penetrating or stricturing complications leading to repeated surgeries and disability. Studies on the natural history of CD provide invaluable data on its course and clinical predictors, and may help to identify patient subsets based on clinical phenotype. Most data are available from referral centers, however these outcomes may be different from those in population-based cohorts. New data suggest the possibility of a change in the natural history in Crohn&#x02019;s disease, with an increasing percentage of patients diagnosed with inflammatory disease behavior. Hospitalization rates remain high, while surgery rates seem to have decreased in the last decade. In addition, mortality rates still exceed that of the general population. The impact of changes in treatment strategy, including increased, earlier use of immunosuppressives, biological therapy, and patient monitoring on the natural history of the disease are still conflictive. In this review article, the authors summarize the available evidence on the natural history, current trends, and predictive factors for evaluating the disease course of CD.

Effects of natural cerebrolysin on protective proteins and pro-apoptotic molecules in mesenchymal stem cells following beta-amyloid peptide1-40-induced endoplasmic reticulum stress

BACKGROUND： Studies have demonstrated that β-amyloid peptide （Aβ）, a characteristic pathological product of Alzheimer＇s disease （AD）, results in neuronal endoplasmic reticulum stress （ERS）. However, the mechanisms of traditional Chinese medicine against ERS in AD are poorly understood. OBJECTIVE： To measure expression levels of protective proteins （GRP78 and GRP94） of ER molecular partners and pro-apoptotic Caspase-12 ER membrane expression following application of traditional Chinese medicine natural cerebrolysin （NC） to treat Aβ1-40-induced ERS. DESIGN, TIME AND SETTING： A parallel-controlled study was performed at the Institute of Integrated Western and Traditional Chinese Medicine, Shenzhen Hospital of Southern Medical University between September 2006 and November 2008. MATERIALS： Sprague Dawley male rats, 6-8 weeks old, were used to harvest tibial and femoral bone marrow. Isolation and purification of mesenchymal stem cells （MSCs） were established from the whole bone marrow by removing non-adherent cells in primary and passage cultures. Aβ1-40 was provided by Sigma, USA. NC was provided by Shenzhen Institute of Integrated Chinese and Western Medicine, China. NC was predominantly composed of Renshen （Radix Ginseng）, Tianma （Rhizoma Gastrodiae）, and Yinxingye （Ginkgo Leaf） in a proportion of 1 ： 2： 2. Following conventional water extraction technology, an extract （1 ： 20） was prepared. Six adult, male, New Zealand rabbits underwent intragastric administration of NC extract （0.976 g/kg per day） for 1 month to prepare NC-positive serum, and the remaining 6 rabbits received intragastric administration of physiological saline to prepare normal blank serum. METHODS： A total of 500 nmol/L Aβ1-40 was used to establish ERS models of primary cultured MSCs. AD cell models were incubated with different doses of NC-positive serum （2.5%, 5%, and 10%）. MSCs treated with normal blank serum served as normal blank controls. MAIN OUTCOME MEASURES： Reverse transcription-polymerase chain reaction and fluorescent immunocytochemistry were respectively used to measure mRNA and protein expression levels of GRP78, GRP94, and Caspase-12 in MSCs. RESULTS： Following Aβ1-40 exposure, mRNA and protein expression levels of GRP78 and GRP94, as well as Caspase-12, significantly increased （P 〈 0.05）, suggesting successful establishment of ERS models. Following NC-positive serum application, mRNA and protein expression levels of GRP78 and GRP94 in MSCs significantly increased （P 〈 0.05 or P 〈 0.01）. However, mRNA and protein expression levels of Caspase-12 significantly decreased （P 〈 0.05, or P 〈 0.01） compared with the ERS model group. These effects were dose-dependent. CONCLUSION： NC downregulated Caspase-12 expression and upregulated GRP78 and GRP94 expression in MSCs in a dose-dependent manner under the state of Aβ1-40-induced ERS.