Multifaceted role of haptoglobin:Implications for disease development

Haptoglobin,a protein primarily recognized for its role in sequestering free hemoglobin,has been identified as a molecule with diverse and underexplored functions in the pathophysiology of various diseases.This editorial explores the multifaceted roles of haptoglobin,highlighting its involvement in inflammatory responses and immune regulation and its potential implications in chronic diseases such as diabetes,cardiovascular disorders,and cancer.Through a synthesis of recent research findings,this editorial reveals the importance of haptoglobin in disease mechanisms and underscores the need for further investigation to fully elucidate its therapeutic potential.A comprehensive understanding of haptoglobin’s novel functions may catalyze the development of innovative diagnostic and therapeutic modalities in clinical practice.

TGF-β and BMP signaling in osteoblast,skeletal development,and bone formation,homeostasis and disease

INTRODUCTIONThe transforming growth factor-β （TGF-β） superfamily com- prises TGF-βs, Activin, bone morphogenetic proteins （BMPs） and other related proteins. TGF-β superfamily members act through a heteromeric receptor complex,, comprised of type I and type II receptors at the cell surface that transduce intracellular signals via Smad complex or mitogen-activated protein kinase （MAPK） cascade.

To unwind the biological knots:The DNA/RNA G-quadruplex resolvase RHAU(DHX36)in development and disease

The G-quadruplex(G4)sequences are short fragments of 4-i nterval triple guanine(G)with frequent and ubiquitous distribution in the genome and RNA transcripts.The G4sequences are usually folded into secondary“knot”structure via Hoogsteen hydrogen bond to exert negative regulation on a variety of biological processes,including DNA replication and transcription,mRNA translation,and telomere maintenance.Recent structural biological and mouse genetics studies have demonstrated that RHAU(DHX36)can bind and unwind the G4“knots”to modulate embryonic development and postnatal organ function.Deficiency of RHAU gives rise to embryonic lethality,impaired organogenesis,and organ dysfunction.These studies uncovered the pivotal G4 resolvase function of RHAU to release the G4 barrier,which plays fundamental roles in development and physiological homeostasis.This review discusses the latest advancements and findings in deciphering RHAU functions using animal models.

Melastatin-related transient receptor potential 2 channel in Aβ_(42)-induced neuroinflammation: implications to Alzheimer's disease mechanism and development of therapeutics

Alzheimer’s disease （AD） is an age-related eurodegenerative disease that represents the most common cause of dementia among the elderly people. With the increasingly aging population, AD has presented an overwhelming healthcare challenge to modern society; the World Alzheimer Report 2015 has estimated that 46.8 million people worldwide lived with dementia in 2015 and this number will rise to 74.7 million in 2030 and that the total cost of dementia was 818 billion in US$ in 2015 and will reach two trillion in 2030. Post-mortem studies have identified two histopathological hallmarks in the brains of AD patients; extracellular senile plaque with elevated deposition of amyloid β （Aβ） peptides, and intracellular neurofibrillary tangle composed of hyper-phosphorylated microtubule-associated protein tau.Etiologically, progressive neuronal loss within the cerebral cortex and hippocampus regions of the brain leads to irreversible decline in, and eventually complete loss of, memory and other cognitive functions that afflict AD patients. The widely-accepted amyloid cascade hypothesis for AD pathogenesis holds that accumulation and aggregation of neurotoxic Aβ peptides, due to imbalance of their generation and clearance as a result of changes in genetic makeup, aging and/or exposure to environmental risk factors, is a major and early trigger of AD. This hypothesis has continuously gained support by preclinical and clinical studies （Selkoe and Hardy, 2016）. However, the intensive and costly drug discovery efforts over the past decades based on such a hypothesis have proved extremely frustrating in developing effective therapeutics to treat or slow down the progress of AD, highlighting the need for more research to improve our understanding towards the cellular and molecular mechanisms by which Aβ peptides bring about neurotoxicity and cognitive dysfunction.

Is it time to rethink the Alzheimer's disease drug development strategy by targeting its silent phase?

Alzheimer＇s disease （AD） is the most frequent cause of dementia in the western world. In clinical terms, AD is characterized by progres- sive cognitive decline that usually begins with memory impairment. As the disease progresses, AD inevitably affects all intellectual functions including executive functions, leading to complete dependence for basic activities of daily life and premature death.

Risk factors for the occurrence and development of Binswanger disease: A controlled observation

BACKGROUND： Some scholars think that hypertension is the major risk factor to cause Binswanger disease （BD）, however, BD is also found in some persons with normal blood pressure, so we presume that some other factors, such as diabetes mellitus, hyperlipemia, coronary heart disease and transient ischemic attacks and so on, might participant in the onset of BD. OBJECTIVE： To comparatively observe the difference in accompanying diseases, transcranial doppler （TCD） performance, blood glucose and blood lipid level between BD patients and healthy subjects who received health examination, and between BD patients with different disease condition. DESIGN ： Case-control analysis SETTING ： Department of Emergency, Qingdao Municipal Hospita PARTICIPANTS： Totally 126 patients with BD, 65 male and 61 female, aged from 67 to 85 years old, who hospitalized in the Medical School Hospital of Qingdao University and Qingdao Municipal People＇s Hospital, were chosen, serving as BD patients group. All the patients met the clinical diagnostic criteria of BD introduced by Bennett et al. Another 126 persons, 65 male and 61 female, aged ranging from 67 to 80 years, who received health examination in the same hospital, were homeochronously chosen, serving as control group. Informed consents were obtained from all the subjects. METHODS ： After being admitted, all the subjects including BD patients and persons who homeochrenously received health examination in the same hospital were given examinations of blood pressure, blood lipid, blood glucose, electrocardiogram （ECG） and TCD. Fifty-seven patients with BD were in the stable period and 69 in the progressive period （Stable period： no local or subcortical function disorder found, and no changes in the range of white matter lesion showed by CT and/or MRI in recent 3 months; Progressive period： with local or subcortical function disorder and increase in the range of white matter lesion showed by CT and/or MRI in recent 3 months）. According to intimal thickening of carotid artery and vertebral artery preformed by TCD, BD was graded as mild intimal thickening （〈 1.1 mm）, moderate intimal thickening （1.1 to 1.2 mm） and severe intimal thickening （〉 1.2 mm）. MAIN OUTCOME MEASURES ： Comparison of the ratio of BD patients with accompanied diabetes mellitus, hypedipemia, coronary heart disease and transient ischemic attacks, TCD performance, blood glucose and blood lipid level between BD patients group and control group, and among BD patients with vadous disease conditions. RESULTS： Totally 126 BD patients and 126 subjects who received health examination all participated in the result analysis. Intergroup comparison： ①The ratio of BD patients with accompanied hypertension, diabetes mellitus, hypedipemia, transient ischemic attacks and coronary heart disease was 91.3%, 46.8%, 42.9%, 81.7% and 46.0% respectively in the BD patients group, and that was 36.5%, 17.5%, 15.9%, 34.1% and 34.1%, respectively in the control group. Significant difference existed between two groups （x^2=86.201, 24.907,25.660,58.620,9.900, P 〈 0.01 ）.②Compared with control group, anterior, middle cerebral and vertebrobasilar arteriosclerosis and insufficient cerebral blood supply existed significantly in BD patients with different disease condition （x^2=40.34,7.585,15.429, P 〈 0.01 ）.③Compared with control group, the level of blood glucose, total cholesterol and triglyceride of BD patients increased significantly （t=6.939,3.891,3.711 ,P 〈 0.01 ）. Comparison among BD patients with different disease condition： ① Compared with stable period, transient ischemic attacks and coronary heart disease were found much in the BD patients at progressive period, with significant difference （x^2=7.196,13.517,P 〈 0.01 ）.② Mild arteriosclerosis at stable period was found in 17 cases, and significant difference existed compared with progressive period （x^2=6.523,P 〈 0.05）.③ There was no significant difference in the blood glucose and blood lipid level （t=-1.755 6,0.583 1,0.824 6, P 〉 0.05）. CONCLUSION： Hypertension, cerebral arteriosclerosis, diabetes mellitus, hypedipemia, coronary heart disease and transient ischemic attacks have important effects on the onset of BD; Transient ischemic attacks and coronary heart disease can worsen the symptoms of BD patients.

Developing biomarkers for neurodegenerative diseases using genetically-modified common marmoset models

Mouse and non-human primate models of neurodegenerative disease：The prevalence of age-related neurodegenerative diseases continues to increase with ever increasing aging population over the age of 60.Although the difficulties associated with neurodegenerative diseases present an urgent global issue,there is no effective treatment for these conditions.

APPLICATION OF PRINCIPLE OF "PREVENTION IN PREFERENCE TO TREATMENT OF DISEASES" IN ACUPUNCTURE-MOXIBUSTION CLINIC

In the present paper the author reviews the viewpoint of 'preventive treatment of diseases' in the ancient literature of traditional Chinese medicine (TCN) and its clinical application from (1) prevention first before the occurrence of diseases; and (2) preventing development after onset of diseases. In the preventive treatment of diseases, the ancient Chinese doctors usually (1) regulated qi of both Conception Vessel and Governor Vessel for health care; (2) performed regular moxibustion; and (3) applied plaster to the acupoint in summer for treating winter-diseases. In the treatment of diseases after onset, the ancient Chinese usually (1) tried best to make early diagnosis and early treatment; and (2) strengthened the related internal organ in advance to check their development; and (3) employed appropriate remedies to recuperate the patient's health.

Human embryonic stem cells as an in vitro model for studying developmental origins of type 2 diabetes

The developmental origins of health and diseases(DOHaD)is a concept stating that adverse intrauterine environments contribute to the health risks of offspring.Since the theory emerged more than 30 years ago,many epidemiological and animal studies have confirmed that in utero exposure to environmental insults,including hyperglycemia and chemicals,increased the risk of developing noncommunicable diseases(NCDs).These NCDs include metabolic syndrome,type 2 diabetes,and complications such as diabetic cardiomyopathy.Studying the effects of different environmental insults on early embryo development would aid in understanding the underlying mechanisms by which these insults promote NCD development.Embryonic stem cells(ESCs)have also been utilized by researchers to study the DOHaD.ESCs have pluripotent characteristics and can be differentiated into almost every cell lineage;therefore,they are excellent in vitro models for studying early developmental events.More importantly,human ESCs(hESCs)are the best alternative to human embryos for research because of ethical concerns.In this review,we will discuss different maternal conditions associated with DOHaD,focusing on the complications of maternal diabetes.Next,we will review the differentiation protocols developed to generate different cell lineages from hESCs.Additionally,we will review how hESCs are utilized as a model for research into the DOHaD.The effects of environmental insults on hESC differentiation and the possible involvement of epigenetic regulation will be discussed.

Human umbilical cord-derived mesenchymal stem cells promote repair of neonatal brain injury caused by hypoxia/ischemia in rats

Administration of human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)is believed to be an effective method for treating neurodevelopmental disorde rs.In this study,we investigated the possibility of hUC-MSCs treatment of neonatal hypoxic/ischemic brain injury associated with maternal immune activation and the underlying mechanism.We established neonatal rat models of hypoxic/ischemic brain injury by exposing pregnant rats to lipopolysaccharide on day 16 or 17 of pregnancy.Rat offspring were intranasally administe red hUC-MSCs on postnatal day 14.We found that polypyrimidine tract-binding protein-1(PTBP-1)participated in the regulation of lipopolysaccharide-induced maternal immune activation,which led to neonatal hypoxic/ischemic brain injury.Intranasal delive ry of hUC-MSCs inhibited PTBP-1 expression,alleviated neonatal brain injury-related inflammation,and regulated the number and function of glial fibrillary acidic protein-positive astrocytes,there by promoting plastic regeneration of neurons and im p roving brain function.These findings suggest that hUC-MSCs can effectively promote the repair of neonatal hypoxic/ischemic brain injury related to maternal immune activation through inhibition of PTBP-1 expression and astrocyte activation.

Mitochondrial replacement techniques or therapies (MRTs) to improve embryo development and to prevent mitochondrial disease transmission

The mitochondrion which contains its own double-stranded circular DNA is a semi-independent organelle that plays critical roles in cell activity. Mitochondrial DNA （mtDNA） is maternally inherited through several mechanisms that have been proposed （Luo et al., 2013） and, if mitochondrial mutations are inherited to the offspring, it is possible to cause mitochondrial diseases such as neuropathy, cardiomyopathy, myopathy, and liver failure.

Emerging functions of tRNA modifications in mRNA translation and diseases

tRNAs are essential modulators that recognize mRNA codons and bridge amino acids for mRNA translation.The tRNAs are heavily modified,which are essential for forming a complex secondary structure that facilitates codon recognition and mRNA translation.In recent years,studies have identified the regulatory roles of tRNA modifications in mRNA translation networks.Misregulation of tRNA modifications is closely related to the progression of developmental diseases and cancers.In this review,we summarize the tRNA biogenesis process and then discuss the effects and mechanisms of tRNA modifications on tRNA processing and mRNA translation.Finally,we provide a comprehensive overview of the physiological and pathological functions of tRNA modifications,focusing on diseases including cancers.

Broad H3K4me3 as A Novel Epigenetic Signature for Normal Development and Disease

The breadth of the enrichment site for post-translational trimethylation of histone H3 at lysine 4 （H3K4me3） on chromatin has attracted great attention recently. H3K4me3, an extensively-studied histone modification, is reported to promote gene transcription by directing preinitiation complex assembly through interaction with effector proteins, e.g.,

Comprehensive understanding of developmental origins of health and disease concepts: Early intervention to non-communicable diseases in China

Introduction Mortality due to various kinds of noncommunicable diseases (NCDs) has become an increasing focus of attention in recent years.1 With rapidly increasing globalization, lifestyles in low-and middle-income countries increasingly include high-fat diets and inadequate physical exercises are resulting in an increased worldwide burden of NCDs.2,3 A study by the International Diabetes Federation (IDF) showed that about 382 million people had diabetes in 2013, and this will rise to 592 million by 2035.The number of people with type 2 diabetes is increasing in every country, and 80％ of people with diabetes live in low-and middle-income countries.The burden of NCDs and the prevalence of related risk factors such asoverweight and diabetes have also increased in China over the past decades.In 2005, NCDs accounted for an estimated 80％ of deaths and 70％ of disability-adjusted life-years lost in China.

Myelin in development and disease

Myelin is an evolutionarUy novel and important structure for the proper functioning of the vertebrate nervous system. In the central nervous system （CNS）, the myelin sheath is elaborated by oligodendrocytes, and is composed of multiple layers of specialized cell membrane wrapping around axons with periodic interruptions at the nodes of Ranvier. The major function of the myelin sheath is to provide ionic insulation to ensure rapid and saltatory conduction of electrical pulses along axons. In addition, myelin provides neurotrophic support for axons, as they become increasingly dependent on myelin-derived signals for survival. Despite the importance of myelin in the functioning of the CNS, oligodendrocytes are particularly susceptible to genetic and environmental perturbations, and demyelination can be triggered by many pathological conditions including traumatic injury, autoimmune disease （multiple sclerosis, MS）, heavy metal toxicity, and hypoxia. Loss of myelin sheaths in the CNS not only results in the compromised conduction of electrical signals, but also causes progressive degeneration of axons and ultimately neuronal loss. Spontaneous myelin repair from immature oligodendrocyte progenitor cells （OPCs） is not effective in demyelinating lesions, due either to the absence of stimulatory developmental signals that are no longer produced in the adult environment, or to the presence of inhibitory factors peculiar to this environment.

Sino-UK Symposium on Developmental Biology and Human Diseases Held in Tsinghua

The Sino-UK Symposium on Developmental Biology and Human Diseases opened in Tsinghua May 6, 2006. TheSymposium, which ran through May 8, 2006, was hosted by the Department of Biological Sciences and Biotechnology, Tsinghua University.

Maternal low protein diet and fetal programming of lean type 2 diabetes

Maternal nutrition is found to be the key factor that determines fetal health in utero and metabolic health during adulthood.Metabolic diseases have been primarily attributed to impaired maternal nutrition during pregnancy,and impaired nutrition has been an immense issue across the globe.In recent years,type 2 diabetes(T2D)has reached epidemic proportion and is a severe public health problem in many countries.Although plenty of research has already been conducted to tackle T2D which is associated with obesity,little is known regarding the etiology and pathophysiology of lean T2D,a variant of T2D.Recent studies have focused on the effects of epigenetic variation on the contribution of in utero origins of lean T2D,although other mechanisms might also contribute to the pathology.Observational studies in humans and experiments in animals strongly suggest an association between maternal low protein diet and lean T2D phenotype.In addition,clear sex-specific disease prevalence was observed in different studies.Consequently,more research is essential for the understanding of the etiology and pathophysiology of lean T2D,which might help to develop better disease prevention and treatment strategies.This review examines the role of protein insufficiency in the maternal diet as the central driver of the developmental programming of lean T2D.

redPATH:Reconstructing the Pseudo Development Time of Cell Lineages in Single-cell RNA-seq Data and Applications in Cancer

The recent advancement of single-cell RNA sequencing(scRNA-seq)technologies facilitates the study of cell lineages in developmental processes and cancer.In this study,we developed a computational method,called redPATH,to reconstruct the pseudo developmental time of cell lineages using a consensus asymmetric Hamiltonian path algorithm.Besides,we developed a novel approach to visualize the trajectory development and implemented visualization methods to provide biological insights.We validated the performance of redPATH by segmenting different stages of cell development on multiple neural stem cell and cancer datasets,as well as other single-cell transcriptome data.In particular,we identified a stem cell-like subpopulation in malignant glioma cells.These cells express known proliferative markers,such as GFAP,ATP1A2,IGFBPL1,and ALDOC,and remain silenced for quiescent markers such as ID3.Furthermore,we identified MCL1 as a significant gene that regulates cell apoptosis and CSF1R for reprogramming macrophages to control tumor growth.In conclusion,redPATH is a comprehensive tool for analyzing scRNA-seq datasets along the pseudo developmental time.redPATH is available at https://github.com/tinglabs/redPATH.

Gene regulatory network inference based on causal discovery integrating with graph neural network

Gene regulatory network (GRN) inference from gene expression data is asignificant approach to understanding aspects of the biological system.Compared with generalized correlation-based methods, causality-inspiredones seem more rational to infer regulatory relationships. We proposeGRINCD, a novel GRN inference framework empowered by graph representationlearning and causal asymmetric learning, considering both linearand non-linear regulatory relationships. First, high-quality representation ofeach gene is generated using graph neural network. Then, we apply theadditive noise model to predict the causal regulation of each regulator-targetpair. Additionally, we design two channels and finally assemble them forrobust prediction. Through comprehensive comparisons of our frameworkwith state-of-the-art methods based on different principles on numerousdatasets of diverse types and scales, the experimental results show that ourframework achieves superior or comparable performance under variousevaluation metrics. Our work provides a new clue for constructing GRNs,and our proposed framework GRINCD also shows potential in identifyingkey factors affecting cancerdevelopment.

Postnatal toxicant exposure in 3xTgAD mice promotes gene x environment-related early alterations to neuroimmune epigenetic profiles

Aim:The purpose of this study was to evaluate sex-biased,maladaptive changes to epigenetic regulation critical for development of neuroimmune crosstalk resulting from an early-life toxicant exposure previously associated with increased susceptibility to later-life neurodegeneration.Methods:An evaluation of early-life gene x environment(GxE)interactions was performed in a mouse model of Alzheimer's disease(Tg)orally exposed to lead acetate(Pb)from postnatal day(PND)5-9.Following exposure,immunohistochemical analysis was used to evaluate hippocampal expression of DAP12,a marker for perinatal microglia related to microglial-mediated postnatal synaptic pruning of neurons.Altered profiles of three microRNAs critical to homeostatic microglia:neuron signaling(miR-34a,miR-124,miR-132)were measured by qRT-PCR.Results:Atypical and deleterious expression patterns in Pb-exposed Tg mice were detected with significant female bias by PND 10.Early exposure to Pb resulted in the upregulation of miR-124,a microRNA involved in microglial quiescence,as well as miR-34a,involved in p53-dependent apoptosis and decreased phagocytosis,by PND 21 and during a period of microglial-mediated synaptic pruning specific to females.In addition,we observed a sustained,imbalanced upregulation of miR-132 in Pb-exposed Tg females as well as decreased expression of DAP12.Conclusion:This study demonstrates the exacerbating effects and early manifestation of GxE interactions in this model.Furthermore,these findings underscore a period of female-specific vulnerability to epigenetic maladaptation during postnatal development,with implications on the faulty later-life adaptability of neuroimmune signaling.Further investigation is warranted to evaluate the persistence and relative contribution of these early influences on the etiopathology of Alzheimer's disease.