Background: There is little research in the literature comparing the efficacy of coblation nucleoplasty with conservative treatment in the treatment of cervical discogenic dizziness and reporting the achieved rate of minimal clinically important differences (MCID) and patient acceptable symptom state (PASS) after surgery. This retrospective study aims to explore the patient-reported outcome measures (PROM) following coblation nucleoplasty for cervical discogenic dizziness and to compare the therapeutic effect of coblation nucleoplasty with prolonged conservative treatment. Methods: Sixty-one patients with cervical discogenic dizziness and a positive intradiscal diagnostic test eligible for single-level cervical coblation nucleoplasty were included in the study. Among these 61 patients, 40 patients underwent cervical coblation nucleoplasty, while the remaining 21 patients refused surgery and received continued conservative treatment. The primary PROMs were the intensity and frequency of dizziness and secondary PROMs were related to the neck disability index (NDI) and visual analog scale (VAS) for neck pain (VAS-neck) during a 12-month follow-up period. Moreover, the achieved rate of MCID and PASS in both groups was assessed 12 months after surgery. Results: Dizziness intensity, dizziness frequency, VAS-neck score, and NDI score were significantly improved from the baseline at all follow-up time points in both treatment groups, except for showing no significant improvement in dizziness frequency in the conservative treatment group at 6 and 12 months after surgery. However, at each follow-up time point, the above indexes were lower in the surgery group than in the conservative treatment group. In addition, the achieved rates for PASS and MCID in all indexes in the surgery group were significantly higher than those in the conservative treatment group at 12 months after surgery. Conclusions: Cervical coblation nucleoplasty significantly improved the intensity and frequency of dizziness, neck pain, and NDI in patients with cervical discogenic dizziness, and the results were superior to those from prolonged conservative treatment. Meanwhile, cervical coblation nucleoplasty is a good choice for patients with chronic neck pain and refractory cervical discogenic dizziness who have not demonstrated the indications for open surgery and have not responded well to conservative treatment. Dizziness is one of the most common reasons that adults seek medical care . TakahasCervical discogenic dizziness should initially be managed with non-surgical treatments, which mainly include physical therapy, manual therapy, vestibular rehabilitation, drug therapy, and acupuncture . The conFrom August 2018 to August 2021, a total of 102 patients with cervical discogenic dizziness who had a positive cervical intradiscal diagnostic test were retrospectively analyzed. Among them, 12 patients underwent non-single-level cervical intradiscal diagnostic tests, 3 patients had incomplete data, 5 patients had cervical trauma, 2 patients had prior cervical surgery, and 19 patients were not suitable for cervical coblation nucleoplasty. Finally, 61 patients eligible for single-level cervical coblation nucleoplasty were included in the study. All patients met the inclusion and exclusion criteria and experienced temporary relief of more than 60% in neck pain and dizziness after an injection of 0.3–0.5 mL bupivacaine into the suspected cervical disc . Among these 61 patients, 40 patients underwent cervical coblation nucleoplasty, while the remaining 21 patients refused surgery and received continued conservative treatment. This retrospective review of prospectively collected data was approved by the Ethics Review Committee of our hospital and followed procedures that were in accordance with the Declaration of Helsinki. Informed written consent was given by all patients.The inclusion criteria for cervical coblation nucleoplasty were as follows: 1) the patient met the diagnostic criteria of cervical discogenic dizziness referred to in our previous review  [1]; (2) the patiPatients were excluded if they met one of the following criteria: (1) they had a history of cervical trauma (including whiplash injury) or surgery; (2) they suffered from neurologic diseases, cardiovascular diseases , vestibular diseases , vision disorders, and any other systematic or severe diseases; (3) they had any demonstrable abnormalities in the congenital or developmental cervical spine; (4) they had cervical instability  ; (5) theCervical coblation nucleoplasty was performed using an anterolateral approach ,15. The The surgical levels involved range from C3–C4 to C6–C7. The distribution of surgical segments in the surgical group was similar to that in the conservative group . In the This study used PROMs to evaluate the treatment benefits. PROMs refer to any reports received directly from patients regarding their health status, without the need for evaluation by clinical doctors or anyone else. The primary PROMs comprised the intensity and frequency of dizziness. The intensity of dizziness was measured with a 100-millimeter visual analog scale (VAS) and the frequency of dizziness was measured on a six-point categorical rating scale  ,10,18. Tt-test was used for the normally distributed continuous data, represented by the mean (standard deviation (SD)). VAS-dizziness, VAS-neck, NDI, and dizziness frequency values were compared between the groups at different time points in the follow-up period using a two-way repeated-measure ANOVA. Prism 8 (GraphPad) was used for the statistical analyses. Statistical significance for the analyses in this study was set at a p-value of <0.05. When comparing the baseline data and the MCID and PASS achieving rates between the two groups, chi-square analysis was used for categorical data, represented by count (percentage), while an independent sample There were no statistically significant differences in age, sex, disease level, and baseline PROMs between the two groups . The avep < 0.001) ) ) . p = 0.050 at 6 months and p = 0.196 at 12 months), except in the first and third months after treatment  in the surgery group were significantly higher than those in the conservative treatment group at 12 months after surgery, indicating that the overall treatment effect of the surgery group was significantly better than that of the conservative treatment group. For most patients with cervical discogenic dizziness, conservative treatments such as manual therapy and physiotherapy are effective. However, a small number of patients with refractory dizziness do not respond to the various conservative treatments and can be treated with surgery on the premise of a clear diagnosis . NumerouIn clinical practice, we found that dizziness was more common in patients who showed simple cervical disc degeneration on imaging but had no disc herniation or spinal cord or nerve compression. The main clinical features of the patients included in this study were mild cervical disc degeneration, along with chronic neck pain and persistent dizziness, that their symptoms, especially refractory dizziness, seriously affected their lives and work, and that they did not respond well to conservative treatment. Subsequently, we performed a cervical intradiscal diagnostic test on each suspected cervical disc to identify the location of symptoms. One day before surgery, the suspected degenerative cervical disc was given an intradiscal diagnostic injection of bupivacaine . The diagnostic test is considered positive only if the symptoms of neck pain and dizziness are relieved by more than 60%, indicating that the suspected disc is the culprit, and the further target disc will be treated with cervical coblation nucleoplasty. A large number of clinical and immunohistochemical studies have found that intervertebral disc degeneration and the ingrowth of Ruffini corpuscles are one of the causes of proprioceptive cervicogenic dizziness ,10,12,13On the other hand, neck pain often causes proprioceptive deficits and neck muscle tension ,25. In cThere are some potential limitations to our study that need to be mentioned. First, because the exact pathogenesis of cervical discogenic dizziness is still unclear, the diagnostic criteria are mainly in terms of exclusivity. Therefore, further studies are needed to evaluate in detail the validity and sensitivity of our proposed diagnostic criteria for cervical discogenic dizziness and the cervical intradiscal diagnostic test. Second, although the use of a cervical brace as a conservative treatment for cervical discogenic dizziness is not an up-to-date treatment strategy, the immobilization provided by a cervical brace can help to improve neck pain  and, thuThis study indicates that cervical coblation nucleoplasty significantly improved the intensity and frequency of dizziness, neck pain, and NDI in patients with cervical discogenic dizziness, and was superior to prolonged conservative treatment. Our study further suggests that intervertebral disc degeneration alone, without cervical spinal cord and/or nerve root compression, can cause cervical discogenic dizziness and pain; thus, a cervical intradiscal diagnostic test can provide support for the diagnosis of cervical discogenic dizziness and ensure good results from coblation nucleoplasty for the treatment of this disease.


The telomeric noncoding RNA TERRA is a key component of telomeres and it is widely expressed in normal as well as cancer cells. In the last 15 years, several publications have shed light on the role of TERRA in telomere homeostasis and cell survival in cancer cells. However, only few studies have investigated the regulation or the functions of TERRA in normal tissues. A better understanding of the biology of TERRA in non-cancer cells may provide unexpected insights into how these lncRNAs are transcribed and operate in cells, and their potential role in physiological processes, such as aging, age-related pathologies, inflammatory processes and human genetic diseases. In this review we aim to discuss the findings that have advanced our understanding of the biology of TERRA using non-cancer mammalian cells as a model system. Eukaryotic chromosomes have evolved specialized nucleoprotein structures termed telomeres to protect their extremities. Mammalian telomeres are constituted by telomeric DNA, telomere-binding proteins forming the shelterin protein complex, and telomeric repeat-containing RNAs, known as TERRA . The telIn mammals, both the double-stranded and the single-stranded telomeric DNA sequences are bound by the shelterin complex which is essential for telomere function and structure. A key role of the shelterin complex is to solve the “end protection problem” that arises from the necessity of cells to discriminate the end of chromosomes from the extremities of DNA double strand breaks (DSBs), occurring due to exogenous and endogenous insults ; 2018. DDue to the inability of the DNA replication machinery to fully duplicate the extremities of linear chromosomes , in the trans, regulating gene expression as well as participating in extranuclear processes  5′ cap  5′ cap . 7% of t) 5′ cap , which d) 5′ cap . While t) 5′ cap . Indeed,) 5′ cap . Which R) 5′ cap   5′ cap . These m) 5′ cap  in human) 5′ cap . FurtherIndeed, the G-rich telomeric tract of TERRA can form stable G-quadruplex (G4) structures composed by the stacking of planar arrangements of four guanines held together by hydrogen bonds  Figure . G4 struTERRA transcription in mammals is tightly regulated by multiple mechanisms. A subset of human subtelomeres contain CpG-island promoters located upstream of TERRA transcription start sites . MethylaSeveral studies indicate that different cell types express different TERRA levels and, importantly, TERRA levels markedly vary among telomeres of a given cell type suggesting that chromosome ends regulate TERRA expression by distinct mechanisms. The study of the telomere-specific regulation of TERRA is fundamental to understanding how the multiple cellular functions of this telomeric lncRNA are coordinated in cells .Investigations of TERRA expression in mammalian non-tumor settings have provided several unexpected findings that critically contributed to our understanding of TERRA biology. Using a CHIRT protocol developed from the combination of ChiRP (Chromatin isolation by RNA Purification) and CHART , Chu and others investigated the genomic binding sites of TERRA transcripts in mESCs . Surprisin situ hybridization (RNA FISH) in mouse mammary epithelial cells and immortalized mouse embryonic fibroblasts (iMEF) revealed that TERRA transcripts accumulate close to the inactive X chromosome  syndrome, a rare autosomal disorder caused by mutations in the gene DNMT3b, represent a striking example of the impact of subtelomeric methylation on TERRA regulation . HypometIntriguingly, mechanisms of TERRA expression regulation have been studied also in human primary tissues and postmitotic cells. In particular, RNA FISH combined with immunofluorescence (IF) enabled the detection of TERRA at telomeres in human muscle biopsies . RT-qPCREmerging evidence using human fibroblasts indicates that TERRA can also exert extranuclear functions mediating the activation of the innate immune response upon telomere shortening. Indeed,  demonstrOnly few studies on TERRA in germline cells are available in the literature most likely due to the complexity to obtain and isolate cells undergoing gametogenesis, especially female oocytes. In germ cells, telomeres not only protect chromosome ends, but they also participate in meiosis. Alterations of telomeric structure or telomere length can affect the formation of gametes . While tInterestingly, RNA FISH/IF experiments have shown that a number of TERRA foci colocalize with TERT in germ cells, independently of the gender . These c−/− mouse are infertile and most of telomeres in Smc1β−/− spermatocytes and oocytes fail to attach to the nuclear envelope during prophase I , the embryonic precursors of germ cell lineages, prior to meiosis. In these cells, TERRA foci number per cell and TERRA transcripts levels increase with gestational age, with female PGCs showing higher TERRA foci compared to male , suggestGerm cells, and in particular oocytes arrested in meiotic prophase I experience chronic oxidative stress . SeveralTERRA detection in germ cells has been mostly studied by RNA FISH experiments. RT-qPCR analyses have been performed in some instances using primer pairs to assess TERRA levels from specific telomeres. While RNA FISH allows the detection of TERRA in single cells, confirming TERRA expression and providing key information on its localization and extent of transcripts clustering, the number of TERRA foci detected by this technique will depend on the experimental settings , making it difficult to compare different studies. Furthermore, the number of TERRA foci will be influenced by the length of the 3′ end of TERRA molecules, which base pairs with the fluorescent probe, and by the extent of clustering of the transcripts. RNase treatment controls are also useful to rule out the possibility that single strand DNA may be detected. These limitations considered, single cell analyses represent a key approach to study RNAs and to directly visualize transcripts at single cell resolution in fixed samples.Indeed, the subcellular localization of TERRA transcripts may be determinant for instructing the alternative functions proposed for TERRA in non-cancer cells. As discussed above, TERRA plays a wide variety of roles that are dependent on the cellular context, the expression levels and localization pattern.The study of TERRA in non-tumor human and mouse cells is contributing to advance our understanding of the mechanisms regulating TERRA expression as well as of its telomeric and extratelomeric functions .Furthermore, several lines of evidence indicate the involvement of TERRA transcripts in the telomere biology of ICF patients derived cells, at least in part through the formation of telomeric RNA:DNA hybrids. Intriguingly, altered metabolism of RNA:DNA hybrids structures has been described in cells from patients carrying other genetic diseases, including amyotrophic lateral sclerosis 4 (ALS4) , ataxia The expression of TERRA in germline cells during meiosis opens the intriguing possibility that this RNA may participate in the meiotic process during gametogenesis. Alterations of telomere structure and shortening of telomeres in germ cells are associated with reduced fertility  due to dStudying TERRA in mammalian models different from cancer cell lines will enable the investigation of new potential roles of these telomeric transcripts in more physiological conditions. Despite the differences in telomere biology between mice and humans, which include longer telomeres and broader expression of telomerase in mouse cells, and the distinct features of TERRA transcription regulation and genomic origins between the two species, mouse models may represent an important tool to decipher the physiological functions of TERRA during embryogenesis and in differentiated somatic cells. Generating TERRA KO models will be a difficult task given to the multiple genomic sites transcribing telomeric repeat-containing RNAs at chromosome ends and PARs. Nevertheless, the study of TERRA in the available conditional knock-out models for TERRA-interacting factors or telomere-binding proteins may help advancing our understanding on TERRA biology and to verify the potential involvement of TERRA in the phenotypes of these mice . These sTherefore, it will be interesting to study TERRA in aging organisms and tissues. Indeed, cancer is considered a disease of aging  and seveTERRA may also play a cell autonomous role in promoting cellular transformation. Indeed, increased expression of TERRA from dysfunctional telomeres has been shown to contribute to DDR activation at chromosome ends , a condiS. cerevisiae and the fission yeast S. pombe (The use of yeast as a model system has been critical to study the biology of TERRA and telomeric R-loops, also during senescence . ExpandiS. pombe ; conversS. pombe . Thus, s


Epilepsy is a common and severe neurological disorder in which impaired glucose metabolism leads to changes in neuronal excitability that slow or promote the development of epilepsy. Leptin and adiponectin are important mediators regulating glucose metabolism in the peripheral and central nervous systems. Many studies have reported a strong association between epilepsy and these two adipokines involved in multiple signaling cascades and glucose metabolism. Due to the complex regulatory mechanisms between them and various signal activation networks, their role in epilepsy involves many aspects, including the release of inflammatory mediators, oxidative damage, and neuronal apoptosis. This paper aims to summarize the signaling pathways involved in leptin and adiponectin and the regulation of glucose metabolism from the perspective of the pathogenesis of epilepsy. In particular, we discuss the dual effects of leptin in epilepsy and the relationship between antiepileptic drugs and changes in the levels of these two adipokines. Clinical practitioners may need to consider these factors in evaluating clinical drugs. Through this review, we can better understand the specific involvement of leptin and adiponectin in the pathogenesis of epilepsy, provide ideas for further exploration, and bring about practical significance for the treatment of epilepsy, especially for the development of personalized treatment according to individual metabolic characteristics. Adipokines, containing various bioactive peptides/proteins, immune molecules and inflammatory mediators, are secreted by adipose tissue and normally function through autocrine, paracrine and endocrine signaling . Leptin Leptin, as a vital regulator in different physiopathologic processes, binds to leptin receptors and activates signaling pathways in the regulating different cellular functions to be neuroprotective. Although mice deficient in the mitochondrial manganese superoxide dismutase (MnSOD or SOD2) exhibit spontaneous seizures , leptin Adiponectin is the 30 kDa adipocyte complement-related protein (Acrp30). Its receptors cover many biological functions. Adiponectin receptor 1 (AdipoR1) and receptor 2 (AdipoR2) have physiological correlations in metabolic processes. T-cadherin, a cadherin superfamily member, is a potent receptor for hexamer and adiponectin oligomers with high molecular weight –12. FullVia bioinformatics technology, researchers used Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) network to reveal that synapses play a crucial role in medial temporal lobe epilepsy (MTLE) . It has Seizures and their potential effects on the development of the brain, especially for patients with clinically intractable epilepsy, may experience varying degrees of cognitive impairment, behavioral abnormalities, or psychiatric symptoms, all of which cause severe limitations in daily lives , 32. HowDysfunction in metabolic processes can bring about changes in neuronal excitability , promotiFebrile seizures(FS) is a common convulsive disease in children. Low-level leptin in cerebrospinal fluid (CSF) is related to the susceptibility to complex febrile seizures . ChronicThe pathogenesis of epilepsy starts from pathophysiological changes to the progression after seizures, including changes in voltage and transmitter-gated channels, intracellular signal cascades, synaptic connection, alteration in gene expression, abnormal protein production and activation or inhibition of the metabolic pathway, etc., which may be targeted indicators for the drug to inhibit epileptogenesis.Leptin is a peptide hormone derived from adipocytes. Leptin receptors are expressed in both neonatal and adult hippocampal neurons, and through the blood–brain barrier (BBB) act in many regions of the central nervous system, where they involve in the regulation of energy balance, inflammatory processes, synapse formation and neurotrophic activity , 40–43. The JAK-STAT pathway is a major signaling mechanism for various cytokines and growth factors. As a family of non-receptor tyrosine kinases, JAK activates and stimulates cell proliferation and apoptosis. After being phosphorylated by JAK, the substrate STAT dimerizes and crosses the nuclear envelope into the nucleus to regulate the expression of related genes . In addiATP) channels transport to the β-cells surface to inhibit glucose-stimulated insulin secretion, thereby increasing K+ conductance and causing β-cells hyperpolarization [Glucose metabolism disorder affects the progression of epilepsy , 49. Leprization .Studies have demonstrated increased glucose uptake in the brain after intravenous leptin administration in wild-type mice . Leptin Leptin involves in energy metabolism through the PI3K-Akt-FoxO1 pathway in neurons . However985 phosphorylates to combine with SHP2 which contains Src homology2 (SH2) domains and SOCS3. SHP2 binds phosphorylated Tyr985 and mediates the activation of ERK in cultured cells. SOCS3 mediates feedback inhibition of LepRb signaling by binding to Tyr985. SHP2 acts as a competitive and negative regulator in the processes of SOCS3's binding to Tyr985 associated with leptin receptors [The expression of Jak1, Stat1 and Stat3 in the hippocampal tissue of epileptic rats induced by lithium-pilocarpine increases . Status eceptors , 68. SHPeceptors . MEK1 execeptors . Nguyen eceptors  found th2+- and voltage-gated K+ channels of large conductance (BK channels) through PI3K [+ channels, decrease after neocortical injection of leptin. Intranasal administration of leptin in mice delays the seizures of generalized convulsions induced by the chemical convulsant PTZ [2+/calmodulin-dependent protein kinase IIα (CaMKIIα) level [In addition to the abnormal release of neurotransmitters, epilepsy is closely related to the highly synchronized abnormal firing of neurons caused by abnormally transmembrane movement of ions. The changes in the structure and function of ion channels lead to excitatory regulation disorder to induce epilepsy. Leptin, however, plays an essential role in different epileptic models. Researchers have found that leptin counteracts the up-regulation of the protein level of the Zn (2 +)/Ca(2 +) signaling, which has a neuroprotective effect in the pilocarpine-induced neonatal Sprague–Dawley rat status epilepticus model  and inhiugh PI3K . The dursant PTZ . Leptin sant PTZ , but alssant PTZ . Ligand-sant PTZ . In hippsant PTZ , pretreaα) level . Other eα) level .2+ influx [Notably, studies have reported the proconvulsant activity of leptin. Intraventricular administration of leptin at a dose of 1 μg in a rat model with penicillin-induced epilepsy increases the mean frequency of epileptiform activity, but never changes its amplitude . Electro+ influx . Experim+ influx  has descAlthough leptin has shown inhibitory and neuroprotective activity against seizures in several epileptic models, it also increases epileptiform activity in other models under certain conditions. Reports on leptin's pro-convulsant and anticonvulsant effects have indicated specific roles of leptin in different epilepsy models and signaling pathways.At present, antiepileptic drugs are still the mainly clinical treatment for epilepsy , 86. AmoAdiponectin is a hormone derived from adipocytes and is released into the circulation  in the fIt has been reported that changes of adiponectin in the central nervous system (CNS) may affect glucose metabolism in hippocampal neurons ; InteresSince glucose cannot freely enter the cell through the lipid bilayer structure of the cell membrane, the transport function of glucose transporters (GLUT) on the cell membrane is necessary to achieve intracellular glucose intake. Glucose is an important energy source for the central nervous system. GLUT1 is expressed in CNS endothelial cells (ECs) and uncoupled with glycolysis in a Notch-dependent manner, and GLUT1 deficiency in stationary adult ECs leads to severe seizures with neuronal loss and CNS inflammation , 102. GLApoptosis and inflammation induced by brain injury are pathogenic factors of epilepsy ; NeverthAdiponectin induces nuclear translocation of NF-κB p65 subunit and phosphorylation of MAPKs in dendritic cells . Zhang eP38 and JNK, another MAPK family member, are homologous protein-serine/threonine kinases, and selective targeting of JNK to P38 has been demonstrated as a potential therapeutic approach to epilepsy . Tai andAntiepileptic drugs may be a potential factor affecting serum adipokine levels , 117. CuSurprisingly, TPM, a novel antiepileptic drug, obviously decreases Leptin/Adiponectin (L/A) ratio and increases serum adiponectin level. Studies have shown that TPM increases energy metabolism and leads to weight loss in children with epilepsy . The conThe specific adiponectin expression in different antiepileptic drugs may be bound up with multiple factors, including obesity, insulin resistance and molecular biology. With the in-depth study of clinical and basic experiments, we expect to deeply understand the specific mechanism of adiponectin to provide the theoretical basis for the clinically individualized treatment of epilepsy.The adverse consequences of epilepsy affect people of all ages, and persistent seizures lead to accidents and even death. The control and treatment of epilepsy are essential to improve the patients' quality of life and to reduce mortality. Peripheral endocrine and metabolic factors regulate seizure threshold and seizure-related pathology by acting on neurons in the central nervous system, triggering intracellular signaling pathways or modulating neuronal activity. The dual role of leptin in epilepsy has attracted researchers' particular attention. On the one hand, the leptin receptor activates related signaling pathways to alleviate seizures and play a neuroprotective role. On the other hand, studies have reported the proconvulsant activity of Leptin in different models of epilepsy. The complex dual effects of leptin in treating epilepsy have brought about a more significant challenge, and its role in epilepsy control and treatment needs to be further studied. The association of leptin and adiponectin with epilepsy highlights the important role of these two adipokines in the pathophysiology of epilepsy pathogenesis. A large amount of evidence is helpful to better understand the complex biological mechanisms of leptin and adiponectin, and to provide ideas and a theoretical basis for the development and clinical application of effective hormone modulators in dealing with epilepsy in the future. We still need to further explore the role of adipokine imbalance in the adjusting effect of signal transduction in the pathogenesis of epilepsy, so as to find new methods and preventive measures for epilepsy.


Adaptation to low Pi condition entails sensing internal and external Pi levels and translating those signals to molecular and morphophysiological changes in the plant. In this review, we present findings related to local and systemin Pi sensing with focus the molecular mechanisms behind root system architectural changes and the impact of hormones and epigenetic mechanisms affecting those changes. We also present some of the recent advances in the Pi sensing and signaling mechanisms focusing on inositol pyrophosphate InsP It can be bound by calcium in alkaline soils, complexed into charged aluminum and iron oxides in acidic soils, or immobilized by organic material  transcription factor activates the ALUMINIUM ACTIVATED MALATE TRANSPORTER 1 (ALMT1), which is integrated into the plasma membrane where it functions as a malate secretion system into the apoplasm  such as inhibition of primary root growth and increased lateral root development in response to low external Pi to augment Pi absorption. These root developmental changes are likely governed in the rhizosphere by mechanisms that are localized to the root, as opposed to systemic sensing wherein alterations in the expression of genes involved in Pi transport and distribution, and sensors such as the SPX domain genes are triggered , cytokinin (CK), gibbberellin (GA), strigolactone (SL) and jasmonate (JA) are other hormones that play significant roles in integrating environmental cues and RSA. ET is a positive regulator of root hair growth and root elongation under Pi starvation , which is a negatively affected mating pheromone signal in yeast when it is truncated, a cyclin dependent kinase (CDK) inhibitor phosphatase 81 (Pho81), and the human Xenotropic and Polytropic Retrovirus receptor1(Xpr1). Xpr1 regulates polyphosphate in platelets and was implicated in thrombosis in vivo  plays an increasingly important role in elucidating the mechanism of Pi homeostasis  and prevents the PHR proteins from entering the nucleus  is activated under Pi starvation and several genes that are involved in the uptake and storage of Pi are upregulated  complex in yeast. This comprises Vtc1, Vtc2, Vtc3, and Vtc4, where Vtc4 is the catalytic subunit  are gaining attention for broadening our understanding of energy metabolism and nutrient sensing in humans as well as plants  can be via lipid-dependent or lipid-independent pathway Fig. A. Lipid-6 synthesis has been characterized well for plants compared to animals. In the first step of the pathway, myo-inositol kinase (MIK) was reported to be involved in phosphorylation of inositol at 3 position to form InsP  to avoid the need for LPA1 enyzme for final product synthesis  is the major source of Pi storage in seeds. Owing to Multidrug Resistance Protein 5 (MRP5) which activates InsP6 transport to the vacuolar membrane, InsP6 can be stored in higher amounts in plants  were assumed to inter-convert InsP6 to InsP7 and InsP7 to InsP8 in two successive steps , PD  and PH (Pleckstrin-homology) domains. Despite limited sequence identity of AtITPKs and PPIP5Ks, KD domain is conserved in these two kinases (Wang et al. 7 and decreased InsP8 levels with stunted growth and Pi sensing defects (Dong et al. PD-KD domains render unique features to PPIP5Ks and their balanced activities are critical for growth, development and Pi sensing in plants (Zhu et al. 8 synthesis (Fig. 8 is a proven metabolic messenger of intra-cellular Pi status across humans and plants (Dong et al. As discussed above, InsPs and PP-InsPs synthesis pathways exhibit similarities and differences among humans and plants at various levels with common downstream InsPsis Fig. B, C. Ins8 synthesis, which eventually facilitated SPX-PHR1 binding and finally transcription of PSR genes is turned off. On the other hand, low cellular Pi leads to a decrease in InsP8 levels and PHR1 is available for the activation of PSR genes (Dong et al. Prior to the Wild et al. study, the SPX domain was considered to have a strong binding affinity directly to Pi. This report changed this notion and showed higher binding affinity of the SPX domain to InsP and PP-InsP compared to Pi and PPi (Wild et al. 7 as well as InsP8 levels were considered to be correlated with levels of cellular Pi (Lonetti et al. 8 levels. Restoration of Pi efflux resulted in Pi efflux rescue, hence, highlighting InsP8 as the main cellular Pi-sensing signal (Li et al. 8 is the ligand that modulates SPX domain interaction which in turn controls PSR gene expression by interacting with a transcription factor or controls Pi efflux directly in humans.In earlier studies on human cells, cellular InsPvis-a-vis the signaling molecules, PP-InsPs, and the sensor, SPX domain, the diversity of SPX domain-containing proteins in plants need to be explored further as presence of an expanded SPX family compared to humans would help define other functions in this sessile group of organisms. Similarly, PP-InsP-SPX interaction should be characterized to define interaction components of other SPX-domain containing protein members. Another challenge is whether a single enzyme should be targeted in PP-InP biosynthesis pathway or PP-InP interactions with other proteins should be focused to have a better view of PP-InsP targets and their interacting mechanisms (Furkert et al. PSR is multifaceted. Therefore, understanding the mechanisms and making use of the knowledge gained in addressing problems of nutrient stress necessitates a multifaceted approach. With significant progress being made in Pi signaling


PubMed was searched with pre-specified terms during the period of 26 May 2023 to 10 July 2023. The final dataset of 142 manuscripts was evaluated for evidence regarding the effect of gestational age and hormonal regulation on the expression of phase II enzymes (n = 16) and drug transporters (n = 38) in the pregnant woman and in the placenta. This comprehensive review exposes gaps in current knowledge of phase II enzyme and drug transporter localization, expression, and regulation during pregnancy, which emphasizes the need for further research. Moreover, the information collected in this review regarding phase II drug-metabolizing enzyme and drug transporter changes will aid in optimizing pregnancy physiologically based pharmacokinetic (PBPK) models to inform dose selection in the pregnant population.The purpose of this literature review is to comprehensively summarize changes in the expression of phase II drug-metabolizing enzymes and drug transporters in both the pregnant woman and the placenta. Using PubMed Physiological changes during pregnancy affect drug pharmacokinetics (PK), including absorption, distribution, metabolism, and elimination . PK chanPhysiologically based pharmacokinetic (PBPK) modeling is an increasingly used method for predicting drug exposure during pregnancy . UtiliziSeveral literature reviews have been published that examine changes in enzyme and/or transporter expression in the pregnant woman and in the placenta. Gestational changes in select phase II enzymes and renal drug transporters have been elucidated through pharmacokinetic analysis of probe drugs administered during pregnancy ,9. AdditThe purpose of this literature review is to comprehensively summarize changes in the expression or activity of phase II enzymes and drug transporters in both the pregnant woman  and the placenta, as currently described in the literature. Where possible, gestational changes are detailed across the three trimesters of pregnancy and postpartum. The effects of hormonal regulation on enzyme or transporter activity are also included in this review. This comprehensive review aims to expand upon the existing knowledge of drug metabolism and transport during pregnancy, aid incorporation of enzyme and transporter changes into PBPK models, and inform predictions of PK changes in the pregnant population. Though more research is necessary to understand the complete landscape of gestational changes in phase II enzymes and drug transporters, the data collected in this review can be utilized to optimize pregnancy PBPK models, especially as Sponsors and Regulators seek to serve this population in drug development programs.The human placenta links the fetus to the mother, providing nutrients to and removing wastes from the fetal circulation . In addiThe human placenta possesses a hemochorial structure, in which the fetal tissue directly contacts maternal blood . The fetBoth passive diffusion and transporter-mediated transfer are involved in the transport of drug molecules across the placental syncytiotrophoblast . The ratDrug transporters are membrane proteins that efflux or influx endogenous and exogenous substances , offerinAlthough drug transporters facilitate the passage of both endogenous and exogenous substrates across cellular membranes, in this review, we focus on the role of drug transporters in the transport of drug substrates. As important contributors to drug PK, drug transporters participate in drug absorption in the gastrointestinal tract; drug distribution to various organs, such as the placenta; and drug excretion by the liver and kidney . Drug trTransporters belonging to the ABC superfamily utilize ATP hydrolysis to efflux drugs from cells ,37. ABC ABCB gene family) . Du. Du21]. Additional experiments conducted with physiologically attainable hormonal concentrations and data collected across gestational trimesters can verify the postulated gestational changes in the expression or activity of UGT1A4, BSEP, MRP3, ENT1, and MRP1.In the following section, clinical observations of maternal plasma concentrations of phase II enzymes or their probe substrates have been utilized as evidence to support the analysis of maternal phase II enzyme expression or activity.While the evidence agrees that there is no significant change in maternal glutathione S-transferase α (GSTA) enzyme expression from preconception through the third trimester of pregnancy ,75, ZustPK data collected following administration of hydralazine  and caffThe search strategy utilized in this literature review was unable to identify studies describing individual changes in activity for UGT1A1, UGT1A3, and UGT2B7, though a study involving buprenorphine metabolism was retrieved. Considering buprenorphine metabolism by UGT1A1, UGT1A3, and UGT2B7, combined maternal enzyme activity appears to increase from the first trimester through the third trimester, then returns to baseline postdelivery; these conclusions are based upon observed changes in the area under the curve (AUC) ratio of buprenorphine glucuronide metabolite to buprenorphine parent drug across gestational trimesters . Due to Because phase II enzymes are critical components in the elimination of many drugs and their metabolites, changes in their activity during pregnancy present consequences to drug safety and efficacy for the pregnant woman. A phase II enzyme that exhibits a gestational decrease in activity will demonstrate decreased conversion of a substrate to its easily eliminated form . This deAs suggested with analysis of placental tissue samples, placental protein carboxyl-O-methyltransferase (CMT) activity increases throughout the first trimester, achieves a peak at the beginning of the second trimester, then decreases until term  54]. Ap. Ap54]. Though it has been suggested that placental phase II enzymes may marginally contribute to maternal drug metabolism and PK , placentIn the following section, clinical PK data for maternal drug transporters are detailed to support the analysis of maternal drug transport expression or activity.P-gp appears to exhibit tissue-specific changes in activity from the third trimester of pregnancy to postpartum . In a diWhile additional data are necessary to confirm renal OAT1, OAT2, and OAT3 activity during pregnancy, the transporters appear to behave differently across gestational trimesters . Peak trNo studies were found regarding individual changes in activity during pregnancy for BCRP, OATP1B1, and OATP1B3. As suggested with rosuvastatin PK data, the collective hepatic activity of BCRP, OATP1B1, and/or OATP1B3 is decreased in the third trimester, returning to baseline by postpartum; these conclusions are based upon the higher mean rosuvastatin AUC values observed in pregnant women during the third trimester compared to AUC values observed at term and postpartum . The comLimited data are available regarding the individual contributions of OCT2, MATE1, and MATE2-K to the vectorial transport of substrates . ConsideGestational changes in drug transporter activity have similar implications to drug safety and efficacy as gestational changes in phase II enzyme activity. A renal drug transporter that exhibits a gestational decrease in apparent activity may decrease renal clearance, increase drug exposure, and elevate the risk of drug toxicity . ConversPlacental tissue obtained following delivery or termination of pregnancy, as well as in vitro cell models, have been utilized to study gestational changes in drug transporter activity, and application of the models is detailed in this section. Most of the evidence supporting placental transporter expression and activity is biological . mRNA expression and protein expression are assumed to translate to transporter activity unless evidenced otherwise.Overall, placental P-gp activity demonstrates peak activity in the first trimester, followed by a decrease through the third trimester  81,82,8,84. IncoPlacental MDR3 expression across each gestational trimester cannot be deduced, though evidence is available to describe a general trend of expressional change from the first trimester through the third trimester. However, this evidence is contradictory, revealing both increased gene expression  and decrGestational changes in placental MRP2 expression cannot be determined due to conflicting evidence . In one Compared to MRP5 mRNA expression in placentas at gestational week 23–32, mRNA expression was significantly lower in placentas at gestational week 32–37 and 6-fold lower in placentas at term  25]. Th. Th25]. Gestational changes in placental BCRP expression remain uncertain . PetroviContradictory evidence regarding the gestational changes in placental OATP2B1 expression does not allow for definitive determination of transporter changes during pregnancy . PlacentA consistent increase in placental OCT3 protein expression from the first trimester to term has been suggested ,91. PlacDecreased placental OCTN2 mRNA expression, though not considered to be statistically meaningful, was observed in third trimester placental samples compared to term placental samples . The lacPlacental OAT4 activity appears to increase from the second to the third trimester , as suggIncreases in fetal IgG concentration and fetal-to-maternal IgG ratio with increasing gestational age suggest increased placental FcRn transport capacity throughout pregnancy . To faciMany of the placental transporters for which data were found demonstrate a general trend of increased , decreased , or unchanged  transporter expression or activity from the first trimester to term . These gIncreased knowledge of placental transporter activity will inform understanding of PK changes in the pregnant woman, as well as potential adverse event risk for the fetus . Drugs cThe screening of manuscripts and the collection of data were not confirmed by a second individual. Because the search was solely conducted using PubMed, there is also the risk that the search criteria did not encapsulate all relevant literature about gestational changes in phase II enzyme and drug transporter activity. To ensure completeness, the search term “pharmacokinetics” was checked in addition to those listed in PK data were available for the maternal phase II enzymes and drug transporters; the summarized PK data can be utilized to aid pregnancy PBPK modeling when no clinical data exist to guide dosing. However, in the absence of available PK data for placental phase II enzymes and drug transporters, in vitro observations  have been utilized to formulate conclusions of gestational changes in placental enzyme and transporter expression or activity. Changes in mRNA expression or protein expression were also assumed to translate to changes in enzyme or transporter activity unless demonstrated otherwise. The assumptions made based upon in vitro observations may require verification with additional evidence before confident application into PBPK models. Specific assumptions are identified in the Discussion.Sparse and conflicting evidence exists regarding the localization, expression, and regulation of phase II drug-metabolizing enzymes and drug transporters across gestational stages. To resolve the uncertainties and assumptions in current knowledge, additional PK data and clinical pharmacology research are required to understand drug metabolism and transport in the pregnant woman and in the placenta. Although this comprehensive review of phase II enzymes and drug transporters exposes gaps in knowledge, the available information of enzyme and transporter changes may aid in optimizing pregnancy PBPK models to improve the accuracy of model predictions, confirm the need for dose adjustments, and optimize the safety of the developing fetus.


Neurodegenerative diseases encompass a heterogeneous group of conditions characterised by the progressive degeneration of the structure and function of the central or peripheral nervous systems. The pathogenic mechanisms underlying these diseases are not fully understood. However, a central feature consists of regional aggregation of proteins in the brain, such as the accumulation of β-amyloid plaques in Alzheimer’s disease (AD), inclusions of hyperphosphorylated microtubule-binding tau in AD and other tauopathies, or inclusions containing α-synuclein in Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Various pathogenic mechanisms are thought to contribute to disease, and an increasing number of studies implicate dysfunction of oligodendrocytes  and myelin loss. Aberrant DNA methylation, the most widely studied epigenetic modification, has been associated with many neurodegenerative diseases, including AD, PD, DLB and MSA, and recent findings highlight aberrant DNA methylation in oligodendrocyte/myelin-related genes. Here we briefly review the evidence showing that changes to oligodendrocytes and myelin are key in neurodegeneration, and explore the relevance of DNA methylation in oligodendrocyte (dys)function. As DNA methylation is reversible, elucidating its involvement in pathogenic mechanisms of neurodegenerative diseases and in dysfunction of specific cell-types such as oligodendrocytes may bring opportunities for therapeutic interventions for these diseases. MOBP as being associated with the risk of multiple neurodegenerative diseases . Ho. Ho29]. Although neurodegenerative diseases such as Alzheimer’s disease (AD) are mainly associated with grey matter and neuronal damage, there is evidence for decline and involvement of white matter during disease progression. Disruption of myelin in AD was described at the beginning of the twentieth century by Alois Alzheimer . It has A direct role for OLGs in neurodegenerative disease is exemplified by the pathology of MSA, where glial cytoplasmic inclusions (GCIs) in OLGs are the pathological hallmark of the disease . In MSA,APOE-ε4) carriers, also demonstrated aberrant deposition of cholesterol in OLGs and dysregulated myelination in AD [Although the precise role of OLGs in AD pathology is less clear, there is evidence from human post-mortem studies that there are alterations in the numbers and morphology of OLG lineage cells in this disease . In poston in AD .BIN1) gene, which is the second strongest genetic risk factor for late onset AD [BIN1 is reported in AD [BIN1 and AD are unclear. Myelin associated oligodendrocyte protein (MOBP) gene has been associated with disease risk in several neurodegenerative diseases, including PSP [APOE-ε4 carriers [MOBP gene in PSP [.GWAS have also implicated specific myelin/OLG-related genes in neurodegeneration, including the bridging integrator 1   Fig. 4aa4a. ThisStudies using immunodetection of 5mC or 5hmC have often failed to lead to consensus regarding the occurrence of global DNA methylation/hydroxymethylation changes in neurodegenerative diseases, possibly reflecting limitations of such techniques , 113. HoWhilst most DNA methylation studies employ ‘bulk’ tissue analysis, more recent studies exploring DNA methylation changes in neurodegeneration have investigated cell-specific alterations. Shireby and co-workers investigated AD-related DNA methylation signatures in purified brain nuclei and found that many AD-related DNA methylation changes that had previously been detected in ‘bulk’ tissue were indeed driven by changes in non-neuronal cells, including in OLGs . This fi. Given that the majority of the DNA methylation sites (CpGs) investigated in these studies were in promoter regions, and given the association of promoter region DNA hypermethylation with decreased gene expression, this supports an important role for DNA methylation in silencing cell cycle and proliferation genes and in activating myelin genes, thus enabling OPCs to leave their proliferative state and differentiate into myelinating OLGs. DNA methylation of specific genes involved in OPC differentiation has also been described. The DNA-binding protein inhibitors Id2 and Id4 showed decreased expression during OPC differentiation in mice, which was correlated with hypermethylation of their promoter regions, suggesting a role for DNA methylation in the silencing of these genes to allow the expression of myelin genes during differentiation [Gene expression changes determined by DNA methylation play an important role in the process of lineage specification from OPCs to mature OLGs , 105. Alntiation . As descntiation , 65, 93 ntiation , 83, 105Tet1 knock-out mice, an effect that appeared to be largely specific to the OLG lineage compared to neurons and astrocytes [DNA hydroxymethylation is also dynamic during the OLG life cycle, and TET1 is one of the enzymes involved in this process Fig. . Slower trocytes . TET1 watrocytes . Interestrocytes . As withtrocytes , 120. Ovtrocytes .More research is needed to elucidate further the importance of 5mC and 5hmC in OLGs, and to understand the complex roles of DNMTs and the TET family of enzymes. This should include investigation of changes in their catalytic activities, during OLG differentiation, in myelination, and in remyelination after injury.MOBP and BIN1) have been associated in GWAS with the risk of developing neurodegenerative diseases. In addition, MOBP was shown to present aberrant DNA methylation in an EWAS of post-mortem MSA white matter tissue [MOBP were found even in brain regions very mildly affected by MSA pathology , indicating that these may reflect early changes and contribute to disease pathogenesis. The methylation status of MOBP in MSA is linked to changes in MOBP expression levels [BIN1 is the second strongest genetic risk factor for late onset AD [BIN1 locus have also been reported [BIN1 transcript levels being associated with β-amyloid load [BIN1 has been shown to be predominantly localised to white matter in the brain and expressed primarily in mature OLGs [BIN1 gene in disease processes may be mediated through DNA methylation changes affecting OLGs.As discussed above, OLG-related genes  is their involvement in iron equilibrium in the CNS. Iron is key for normal CNS function , and OLGThere is an increasing understanding of the importance of myelin and OLGs in the pathogenesis of various neurodegenerative diseases, both in those with or without obvious OLG pathology. There is mounting evidence showing that the efficient development, proliferation, differentiation, and maintenance of the OLG lineage cells may be disrupted in disease, and that aberrant DNA methylation is implicated Fig. . WhetherAlthough EWAS have uncovered several aberrantly methylated genes across multiple neurodegenerative diseases, most of these studies utilised bulk tissue, limiting cell-type specific inferences. However, exciting recent advances in cell-type deconvolution algorithms and techniques allowing characterisation of DNA methylation changes in purified cell types or even in single cells will no doubt enhance the discovery of cell-type specific disease-associated DNA methylation signatures.The study of DNA methylation in neurodegenerative diseases is an exciting avenue. On one hand, elucidating pathogenic mechanisms in disease could provide targets for therapeutic intervention. On the other hand, given that DNA methylation is potentially modifiable, and novel techniques to edit DNA methylation in specific genomic sites are emerging , 89, 97,


The global burden of type 2 diabetes (T2DM) has led to significant interest in finding novel and effective therapeutic targets for this chronic disorder. Bioactive food components have effectively improved abnormal glucose metabolism associated with this disease. Capsaicin and zinc are food components that have shown the potential to improve glucose metabolism by activating signalling events in the target cells. Capsaicin and zinc stimulate glucose uptake through the activation of distinct pathways ; however, calcium signal transduction seems to be the common pathway between the two. The investigation of molecular pathways that are activated by capsaicin and zinc has the potential to lead to the discovery of new therapeutic targets for T2DM. Therefore, this literature review aims to provide a summary of the main signalling pathways triggered by capsaicin and zinc in glucose metabolism. Diabetes is the most common metabolic disorder and is a major global health issue ,2. In 20T2DM is the result of genetic and/or environmental factors . The worIR is identified as an impaired response of the target tissues, primarily the liver, adipose tissue, and skeletal muscle, to insulin-stimulated glucose uptake . The halMaintaining normal blood glucose concentrations requires an accurate balance of glucose utilisation and endogenous glucose production by liver or dietary glucose intake . PeripheCurrent antidiabetic agents induce various side effects, such as nausea, bloating, diarrhoea, and risk of hypoglycaemia, which suggest limitations in existing pharmacotherapy and a need for the development of more effective therapies . Many foCapsaicin (8-methyl-N-vanillyl-6-none amid) is a phenolic active compound of chilli peppers responsible for their beneficial impacts on the regulation of glucose homeostasis ,24,25,26Similarly, studies have shown the antidiabetic effects and advantageous impacts of zinc on glucose metabolism ,31,32,33Due to the critical role of signalling pathways in the control of glucose metabolism, several studies have been conducted to understand signalling events leading to the regulation of glucose homeostasis ,38,39. MWhile this research suggests several advantageous effects of capsaicin and zinc on the control of glucose homeostasis, the molecular mechanisms and subsequent pathways are not completely understood. Capsaicin has been demonstrated to regulate glucose metabolism through calcium/calmodulin-dependent protein kinase 2 (CAMKK2) /AMP-activated protein kinase (AMPK) signalling without having any impact on the activation of insulin signalling proteins ,42. In cCalcium is a vital second messenger responsible for a wide range of cellular processes, including glucose homeostasis . AdditioThis review discusses the significance of glucose metabolism and disorders associated with abnormal glucose homeostasis and highlights signalling pathways activated by capsaicin and zinc in the regulation of glucose homeostasis with a focus on calcium signal transduction. In the end, we debate calcium signalling as a possible common pathway between capsaicin and zinc, which could potentially be targeted as a novel therapeutic strategy for IR and T2DM.Owing to its high molecular weight, glucose cannot freely diffuse through the cell membrane. Thus, insulin regulates glucose transfer across the cell membrane through glucose transporter proteins (GLUTs). Any impairment in the function or expression of GLUTs can lead to insulin resistance . For exaAlthough the PI3K/AKT pathway activated by insulin plays a crucial role in cellular metabolism and its dysregulation is related to many diseases, namely IR and T2DM , other eT2DM is a major metabolic disorder that is characterised by IR and a persistent increase in blood glucose levels ; its devIR manifests in peripheral tissues through various mechanisms ,60,61. ISkeletal muscle plays an essential role in glucose uptake and is one of the primary sites of IR ,57. In iExtensive research on IR and T2DM has improved our knowledge of the pathogenesis of these disorders, which led to the development of therapeutic agents . HoweverPrevious studies have shown the beneficial effects of chilli peppers on the improvement of glucose metabolism ,24. ReguTRPV1 is a member of the transient receptor potential (TRP) family of cation channels with six putative transmembrane domains and a calcium-permeable region ,77,78. TSeveral in vivo and in vitro studies have been conducted to discover the mechanism of action of capsaicin in the regulation of glucose metabolism; however, the number and nature of capsaicin-stimulated pathways are still unknown; therefore, more research is needed. Animal studies have demonstrated some mechanisms by which TRPV1 activation by capsaicin improves glucose homeostasis. These include the reduction in inflammatory factors, stimulation of insulin secretion, and activation of signalling molecules involved in glucose uptake ,84,85,86In vitro research has also shed light on the mechanism of action of capsaicin in glucose metabolism ,28,42. CWhile increasing evidence supports the beneficial role of calcium signal transduction induced by capsaicin in glucose uptake, the downstream signalling events by which calcium mediates GLUT4 translocation to the cell membrane and glucose uptake have not been fully studied. Given the apparent effects of capsaicin on glucose homeostasis and because of the crucial role of calcium signal transduction in glucose metabolism, studying the calcium signalling mediated by capsaicin could be an attractive therapeutic target to combat hyperglycaemia linked with IR and T2DM.Zinc is an essential micronutrient that is found in many food groups, including meat, fish, legumes, and dairy. In humans, zinc is the second most abundant trace metal in the body and can be found in all tissues . Zinc isZinc plays a critical role in the formation, crystallization, and stimulation of insulin secretion from pancreatic β cells . Zinc alMaintenance of cytosolic zinc levels regulated by zinc transporters mediates cellular signalling that is amendable to glucose homeostasis and therefore has implications for IR and T2DM ,94. SeveExtracellular zinc triggers the release of calcium from intracellular stores in HT29 cells. This is mediated by the activation of phospholipase-C (PLC) in response to extracellular zinc binding to G-coupled zinc-sensing receptors on the cell surface. This activation leads to the breakdown of PIP2, which generates two important second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), which work together to promote calcium release from intracellular stores. . Like exAlthough studies performed on the mechanism of action of capsaicin and zinc indicate that the pathways activated by these two bioactive food components are distinct, the effectiveness of both capsaicin and zinc in the stimulation of calcium signal transduction suggests this is a common pathway between these molecules.Calcium is a crucial micronutrient and second messenger responsible for a variety of cellular processes, including cell proliferation, differentiation, migration, gene transcription, and cell death . The balCalcium exerts its beneficial effect on glucose homeostasis by activation of calcium signalling protein kinases including CAMKKs and AMPK. Calcium signal transduction also regulates the activity of multiple transcription factors ,48,49. CRecent work has shown that the separate treatment of capsaicin and zinc induces an elevation in intracellular calcium levels in mouse skeletal muscle cells. Moreover, this research revealed the critical role of increased intracellular calcium levels in the activation of signalling proteins, including CAMKK2, CREB, and TORC1, which eventually leads to glucose uptake in these cells .Studying cell signalling involved in glucose metabolism could help to identify new therapeutic targets for diseases associated with abnormal glucose metabolism. Bioactive food components are proposed to have beneficial impacts on human health through the activation of cell signalling events. Many attempts have been made to investigate the effectiveness of capsaicin and zinc as valuable bioactive food components in the improvement of glucose homeostasis ,122,123.Research suggests that zinc and capsaicin stimulate the activation of the signalling events associated with maintaining glucose homeostasis in target tissues including skeletal muscle ,29. ZincConsidering the evaluated impacts of zinc and capsaicin on the control of glucose metabolism, these bioactive components are valuable molecules in insulin-independent glucose uptake. Utilising alternative pathways activated by zinc and capsaicin, which stimulate glucose uptake independently of insulin, could potentially improve glycaemic control in T2DM individuals. However, further work on the mechanism of action of zinc and capsaicin in glycaemic control is required. For example, the expression of TRPV1 on metabolically active tissues such as skeletal muscle makes capsaicin-induced activation of this cation channel an interesting target in drug design for glucose metabolism abnormalities associated with IR and T2DM. ZIP7 is also implicated in the regulation of several genes and proteins involved in glucose homeostasis, which suggests that this zinc transporter could be an effective target for the improvement of glucose metabolism in disorders associated with abnormal glucose homeostasis. Therefore, further work to investigate the impact of TRPV1 and ZIP7 on cellular processes involved in glucose metabolism would help in the development of therapeutic agents targeting these proteins. For instance, enhancing or inhibiting TRPV1 and ZIP7 expression by their transfection could elucidate the function of these genes in the expression of key signalling molecules such as AMPK, CAMKK, AKT, and TORCs, as well as the glucose uptake rate in the cells.In conclusion, there has been an increasing interest in applying bioactive food components for the treatment of disorders associated with abnormal glucose metabolism, including IR and T2DM. Research on signalling events activated by capsaicin and zinc in glucose metabolism has demonstrated that they improve glucose metabolism by activating signalling pathways, including AMPK, AKT, and calcium signal transduction, independent of insulin in skeletal muscle. Although many attempts have been made to understand signalling pathways activated by capsaicin and zinc in glucose metabolism, several signalling events remain uncovered. Therefore, further study of the mechanism of action of capsaicin and zinc on glucose metabolism will require enhanced knowledge of the molecular mechanisms underlying glucose homeostasis in the normal, IR, and T2DM tissue, as well as the development of novel therapies for these disorders.


Dianthus caryophyllus L.) flowers probably originated in the Mediterranean region and certainly were known by the ancient Greeks; the word dianthus is attributed to Greek botanist Theophrastus and refers to dios (divine) and anthos (flower). Since ancient times and through the middle ages, carnations have appeared in art, literature, and ceremonies to become a part of modern pop culture. Today, carnations are economically one of the most important cut flowers  is a well-known mark traditionally connected to transcriptional activation . HistonePlant Physiology, In this issue of DcATX1 promotes ethylene-controlled petal senescence while silencing of DcATX1 postpones it. According to the eFP database, compared with other members of the same methyltransferase family, Arabidopsis  ATX1 has higher expression levels in petals during later stages of flower development  protein—DcATX1—is stabilized by ethylene and throughout senescence. By combining the genetic approach and ethylene treatment experiments, the authors showed that overexpression of elopment . Using cIn an attempt to identify downstream targets of DcATX1-mediated methylation changes, Research connecting ethylene signaling and epigenetics opens space for novel insight into traditionally well-documented developmental mechanisms like petal senescence. Taken together, the elegant experiments reported by


Schwannoma is a benign tumor that originates from the cells of nerve sheaths. The occurrence of mobile schwannoma of the lumbar spine is extremely rare, and when clinicians perform spinal explorations in the expected locations, the results are often negative. This report presents a case of mobile schwannoma in the lumbar spine, aiming to remind doctors to consider the possibility of tumor migration during preoperative planning, thereby avoiding secondary harm to the patient.A 48-year-old male patient presented with a 2-year history of lower back pain and numbness in both lower extremities, which has progressively worsened over the past 3 months. An Magnetic resonance imaging scan revealed an oval-shaped lesion located in the L2/3 vertebral segment, which migrated to the L3/4 vertebral segment following contrast enhancement. The patient underwent tumor resection surgery, and the diagnosis of schwannoma was confirmed through pathological examination.Clinical physicians should increase their understanding of mobile schwannoma of the lumbar spine and utilize imaging techniques to accurately locate the tumor before surgery, in order to avoid unnecessary surgical scope and the risks of additional surgery. Schwannomas are uniformly distributed among various spinal segments and do not show any specific preference for a particular area of the spine. In general, intraspinal Schwannomas rarely metastasize, this article reports a case of a mobile schwannoma of the lumbar spine and provides a systematic review of all cases through PUBMED to improve clinicians understanding of this disease.A Schwannoma, also known as a Schwann cell tumor, is a benign tumor originating from Schwann cells of the nerve sheath. It is commonly seen as a single mass with a complete capsule and represents about 25% of all spinal tumors within the spinal canal.1WI and slightly high signal on T2WI and fat-suppression sequence  of the lumbar spine performed at an outside hospital showed a lesion at the lower border of the L2 vertebral body within the spinal canal. Physical examination revealed slightly hyperactive biceps and triceps tendon reflexes and bilateral Hoffmann signs (+). The lumbar lordosis was flattened, and there was tenderness and right-sided radicular pain upon palpation of the L5/S1 spinous process and paraspinal area, radiating to the right buttock and posterior thigh. Bilateral knee tendon reflexes were reduced, and the dorsiflexion of the foot and ankle muscles was weakened to approximately grade IV . Electrophysiological testing showed evidence of left lower limb radiculopathy involving the L5 root and right anterior tibial muscle. Laboratory tests showed no abnormalities. MRI plain scans showed an elliptical abnormal signal in the spinal canal at the L2/3 level, with slightly high signal on TThrough a posterior midline approach, a tumor resection was performed, along with laminectomy and durotomy at the L3/4 level. The cauda equina was explored, and a spindle-shaped mass was identified with a bundle of nerves passing through the center Fig. C and D.  In 1974, Tomimatsu reported the first case of an intradural-mobile schwannoma, and since then, 29 cases have been reported  years, and 1 case with no reported age and gender. The most common location of the lesion was in the lumbar region (60%), followed by the thoracic region (17%), the thoracolumbar junction (13%), the cervicothoracic junction (7%), and the cervical region (3%). It was observed that all tumors migrated rostral (43%), caudal (43%), or moved back and forth within the spinal canal (13%). The migration distance was within 1 vertebral body in 63% of cases, between 1 and 2 vertebral bodies in 27%, and bigger than 2 vertebral bodies in 10%. One case resulted in entrapment due to migration toward the caudal region after trauma. Clinical symptoms mainly included lower back pain and radiating leg pain with numbness. The activity of the tumor was rarely evident in clinical presentation, and only 3 cases have been reported in the literature, in which symptoms worsened after tumor migration and were related to changes in position or posture, and Valsalva maneuver.,6,9In 1963, Wortzman reported the first case of an intradural-mobile tumor, which was a myxopapillary ependymoma with a distended filum terminale.,14,23,24 In most cases, there are no attachments within the dura mater, and the only restriction for the tumor is the roots connecting the 2 ends. Since there is no spinal cord in the lumbar region, the nerve roots can float in the cerebrospinal fluid, and tumors attached to the redundant cauda equina can have greater mobility. Moreover, when the lumbar spine and buttocks are in an extended position or the weight of the tumor is significant, it can cause the nerve roots to become lax, which can increase the mobility of the attached tumor.,26 Change in posture is also another reason, Isu et al observed tumor activity after gradually changing patient posture and performing repeated MR imaging. Pau et al also observed migrating tumors after changing patient posture following myelography. Therefore, having the patient perform provocative movements, such as back extension, flexion, and jumping, may help detect tumor mobility. Spinal cord deformities caused by extradural tumors may cause corresponding abnormal dilation of the subarachnoid space, 3 cases have been reported in the past, all occurring in the cervical-thoracic region.,11,18 Comparable to the lumbar region, the cervical-thoracic region has a narrower subarachnoid space and shorter nerve roots, so the degree of dilation is often smaller, which may also explain why mobility tumors in the cervical-thoracic region are rarer than in the lumbar region. Some authors have proposed that the Valsalva maneuver can cause tumor movement, and our group has reported 6 cases, all of which moved caudal.,9,13,14 Valsalva maneuver is an action that increases intra-abdominal and intrathoracic pressure by muscle contraction and breath-holding and can be triggered during forceful urination or defecation. The reason why all 6 patients had tumors moving downward may be due to an increase in intra-abdominal pressure causing the tumor to move downward. It has also been reported that the push force of the contrast agent during myelography can cause tumor migration.,6 However, myelography has been replaced by MRI in current preoperative evaluations, and myelography was not used in this case.Several hypotheses have been proposed to explain the reasons for intradural tumor migration, and literature reports have observed redundancy of the cauda equina during myelography.,18 and several authors have reported experiences with second surgeries.,14,17,22 Accurate preoperative localization can reduce the extent of laminectomy and durotomy, as well as the risk of infection and complications for the patient. Currently, various intraoperative or perioperative examinations play a significant role in confirming the precise location of the tumor, such as intraoperative ultrasound, intraoperative MRI, and myelography.,12,13 In the past, myelography was previously considered the gold standard for diagnosis, but the injection of contrast agents can only be completed before opening the dura, and the injection force itself can cause tumor movement, leading to its reduced use. Intraoperative MRI can provide excellent resolution and real-time guidance, but most hospitals do not have this equipment. Friedman confirmed that intraoperative ultrasound helps locate extradural tumors before opening the dura, but it requires higher skills from the operator. Kim suggested that the Valsalva maneuver may help reveal the tumor in situations where there is a lack of imaging modality during surgery.Accurate localization of a tumor before entering the subdural space is crucial for the removal of a mobile intradural tumor, which requires a durotomy and laminectomy. Hollin and Terada reported performing additional laminectomies, with Hollin resection reaching the T12 to L5 level,This study has the following limitations; This study did not conduct long-term follow-up of patients, which limited the evaluation of long-term efficacy and side effects; Patient individual differences in case reports may be large, including age, gender, health status, etc, which may affect the interpretation and promotion of results; Generally speaking, positive or abnormal cases are easier to report and publish, while ordinary or negative cases may be ignored, resulting in publication bias.We reported a case of mobile schwannoma of the lumbar spine, which is a rare disease that clinicians should be aware of. Accurate preoperative diagnosis is particularly important to avoid unnecessary laminectomy and repeated surgeries. Intraoperative MRI, intraoperative ultrasound, myelography, and Valsalva maneuver can all help detect the lesion. When the surgeon does not find the tumor at the site of the dural opening, the possibility of lesion migration should be considered.Data curation: Wanqiu Lyu.Investigation: Xiaojing Li.Supervision: Liyuan Chen.Writing – original draft: Shaowen Song.Writing – review & editing: Binqing Zhang.


Arabidopsis thaliana) (Plants have a love-hate relationship with iron (Fe) and copper (Cu). Due to their redox-active nature, these metals are indispensable as cofactors for a wide range of enzymes and crucial for photosynthesis and respiration, among others. However, Fe and Cu can catalyze the formation of highly reactive hydroxyl radicals, posing a serious threat to plant cells if left unchecked. Hence, plants rely on various mechanisms to control intracellular concentrations of these metals and regulate their uptake to make sure cellular Cu and Fe demands are met while avoiding toxicity . Furtherhaliana) .Ju-Chen Chia and colleagues (opt3 mutant contained significantly higher Fe and Cu levels compared to those of wild-type (WT) plants. Within opt3 leaves, metal accumulation had shifted from the phloem to the xylem and fascicular cambium, and Cu concentrations were significantly lower in the phloem of the opt3 mutant compared to the WT, suggesting the involvement of OPT3 in Fe and Cu loading into the phloem. Furthermore, the authors showed that OPT3 mediates Cu uptake in heterologous systems. As Cu concentrations in the roots, young leaves, and seed coats of developing seeds were also lower in the opt3 mutant, they hypothesized that OPT3 contributed to Cu redistribution from source to sink tissues.In this issue of The Plant Cell, lleagues  reveal tlleagues . They shopt3 mutant was more sensitive to Cu deficiency and that its roots and young leaves expressed typical Cu deficiency-responsive genes to higher levels compared to those of WT plants, even when grown under Cu-sufficient conditions. These symptoms were rescued by transferring the plants to a nutrient solution with a higher Cu concentration. Although mature leaves of opt3 contained higher Fe and Cu levels compared to WT plants, opt3 roots showed a transcriptional Fe and Cu deficiency response, supporting a role for OPT3 in systemic signaling of not only Fe but also Cu. This hypothesis was supported by reciprocal grafting experiments, showing that functional OPT3 in shoots is sufficient to regulate transcriptional Cu and Fe deficiency responses in roots. Interestingly, feeding either Cu or Fe via the shoot phloem partially mitigated both Cu and Fe deficiency responses in opt3 roots. In addition, feeding Cu- or Fe-deficient WT seedlings with Cu or Fe via the phloem in leaves downregulated the expression of both Cu and Fe deficiency marker genes in roots. These data support the existence of shoot-to-root Cu signaling and suggest that Cu and Fe can partially mimic each other's functions in shoot-to-root signaling via OPT3, adding to the complexity of Cu-Fe crosstalk.Next, they showed that the opt3 mutant as a consequence of low Cu and Fe concentrations in the shoot phloem and low Cu concentrations in roots. The resulting Fe overaccumulation in roots might in turn negatively affect Cu uptake.To unravel the interaction between these metals, the authors exposed WT plants to Cu deficiency and Fe deficiency individually or simultaneously. Cu deficiency enhanced Fe accumulation in both roots and shoots. Interestingly, Fe levels were higher in WT plants grown under combined Cu and Fe deficiency than in plants grown under Fe deficiency alone. Furthermore, exposure of WT plants to high Fe concentrations in the growth medium resulted in lower Cu accumulation in roots and shoots. Based on these results, the authors propose that Fe uptake is stimulated in the Taken together, this work revealed that besides its role as an Fe transporter, OPT3 contributes to Cu loading into the phloem and mediates systemic signaling of Cu and Fe status from source to sink tissues. How Cu and Fe specifically transduce such signals remains a topic for further study. The knowledge obtained in this study can benefit the development of strategies to boost crop yield on Cu- and Fe-deficient soils and enhance Cu and Fe levels in edible parts of plants to improve their nutritional value.


Down syndrome (DS), caused by triplication of chromosome 21, is the most frequent aneuploidy observed in the human population and represents the most common genetic form of intellectual disability and early-onset Alzheimer’s disease (AD). Individuals with DS exhibit a wide spectrum of clinical presentation, with a number of organs implicated including the neurological, immune, musculoskeletal, cardiac, and gastrointestinal systems. Decades of DS research have illuminated our understanding of the disorder, however many of the features that limit quality of life and independence of individuals with DS, including intellectual disability and early-onset dementia, remain poorly understood. This lack of knowledge of the cellular and molecular mechanisms leading to neurological features of DS has caused significant roadblocks in developing effective therapeutic strategies to improve quality of life for individuals with DS. Recent technological advances in human stem cell culture methods, genome editing approaches, and single-cell transcriptomics have provided paradigm-shifting insights into complex neurological diseases such as DS. Here, we review novel neurological disease modeling approaches, how they have been used to study DS, and what questions might be addressed in the future using these innovative tools. We sit at an intersection of several complementary technologies including human pluripotent stem cells, genome editing tools, 2D and 3D culture of human stem cell-derived brain cell types, human-mouse chimeras, and single-cell transcriptomics. The combination of these technologies has permitted robust and rapid modeling of human neurological disorders and greater sensitivity to detect phenotypic differences, collectively enabling the field to uncover mechanistic details of human neurological diseases.Down syndrome (DS), caused by triplication of human chromosome 21 , is a coStudies utilizing human postmortem tissue samples have provided a wealth of information related to the anatomical and cellular underpinnings of DS but these samples represent a clinical end-point that rarely allows for cause-and-effect analysis. A number of DS mouse models have been developed that enable mechanistic studies related to the consequence of trisomy 21 on neurodevelopment and brain function. However, the genes found on human chromosome 21 are distributed across a number of mouse chromosomes, which has challenged the generation of a mouse strain that effectively models the genetics of DS. While we have made great strides in this area, biochemical differences in protein sequence and physiology between humans and mice result in a failure of mouse models to accurately mimic human diseases with neurodevelopmental and neurodegenerative components like DS. In light of this, we still lack a detailed understanding of the molecular mechanisms that contribute to disease pathogenesis, which is underscored by the lack of effective therapeutics to alleviate the neurological features of DS.in vitro. Advances in 2D- and 3D-culture systems have paved the way for novel discoveries related to human brain development and function  and impacts approximately 1 in 700 live births . ID in DClinical features of DS present with varying severity and penetration in the population, despite the disorder consistently stemming from triplication of chromosome 21 . While sIn spite of this, some features are consistent, including the fact that individuals with DS exhibit atypical neurodevelopment with effects that persist into adulthood . The mosPostmortem analysis of DS brains indicates brain alterations as early as 15 gestational weeks (gw)  and reduPrecise regulation of neuronal ensembles is critical to support fundamental cognitive processes such as learning and memory and relies on the appropriate generation of neuronal subtypes, neuronal maturation and synaptogenesis, as well as the modulation and sculpting of neuronal circuits by other brain cell types . At the cellular level, the process of neuronal maturation is altered in infants and adolescents with DS  and cortIndividuals with DS are a high-risk group in terms of susceptibility to and severity of infection. Both innate and adaptive immune systems are implicated in the immune dysregulation observed in DS . Chronicin vitro  in rodents due to species-specific genetic differences. This has made rodent modeling of DS-AD a challenge, as complex breeding strategies are required to obtain rodents harboring a genetic background that is capable of presenting a pathology similar to what is observed in humans.Rodent models of human neurological disorders are only as useful as their ability to recapitulate disease phenotypes. While several DS mouse strains model some aspects of the disorder and have provided significant insight into the cellular and molecular mechanisms underlying those specific phenotypes, there does not exist a single model that exhibits all of the clinical features observed in humans with DS [reviewed in ]. There Human iPSCs represent an exceptional model system to study the molecular and cellular underpinnings of neurological disorders. Any cell type can theoretically be differentiated from iPSCs, which can be derived from any individual using non-invasive procedures. More advanced 3-dimensional (3D) culture systems enable co-culture of different brain cell types and patterning factors can be used to generate brain region-specific organoids. While these systems do not allow for behavioral read-outs like rodent models provide, progress in the area of human-mouse chimeras may enable these types of studies. Below, we review current iPSC-derived brain culture systems and highlight application of these systems in the context of DS. Finally, we propose how emerging iPSC-derived culture technologies can help expand our knowledge of the cellular and molecular mechanisms underlying neurological deficits in DS.It has been almost 3 decades since the first reports demonstrating successful conversion of differentiated somatic human cells into stem cells using the reprogramming factors OCT4, SOX2, KLF4, and cMYC (OSKM), referred to as induced pluripotent stem cells (iPSCs) . Human iThe barrier of genetic variability has largely been overcome with the generation of isogenic lines through improved single-cell cloning methods and novel genome editing techniques such as CRISPR-Cas systems. Genome editing enables the precise introduction or correction of pathogenic variants into endogenous genetic loci, and subcloning of parental and modified lines results in the generation of isogenic lines that are identical except for the genetic change of interest. In the context of DS, the first isogenic lines were described by several groups in 2012 and 2013  wherein in vitro differentiation experiments. Several studies have utilized isogenic DS iPSC lines to study various aspects of the disorder in vitro. In the majority of cases, fibroblasts or blood cells were isolated from individuals with DS for reprogramming. More recently, a group demonstrated the utility of reprogramming urine-derived epithelial cells into iPSCs . These protocols attempt to mimic in vivo differentiation programs and, in general, are quite successful in guiding cell fate choices. This is especially true for progenitor populations, such as neural progenitor cells (NPCs), which can be generated by dual suppression of mothers against decapentaplegic (SMAD) inhibition in approximately 3 weeks  overexpression  are a heterogeneous population of cells that give rise to the exquisitely diverse set of neurons and glia of the central nervous system. One of the most efficient and common methods to differentiate human stem cells into NPCs is through dual SMAD inhibition . SMAD siNPCs differentiated from DS iPSCs exhibit reduced proliferation , alteredTaken together, given that NPCs give rise to the major cell types of the brain besides microglia, results from DS iPSC-derived NPCs suggest progenitor cell dysfunction that could explain the clinical finding of reduced brain size and altered frequency of specific brain cell types such as neuronal (excitatory versus inhibitory) and glial  populations. It remains unclear why NPCs are more vulnerable to T21 than other cell types  and how exactly T21 alters fate specification of NPCs. Future studies utilizing both 2D monocultures of NPCs as well as organoids (see 3D models section below) will be useful in addressing these remaining questions.NGN2, which results in neuronal cultures in under 2 weeks   , and somor (NGF) . In all NGN2) neuronal differentiation resulted in increased apoptosis of T21 neurons that was associated with dysregulated protein homeostasis and upregulation of endoplasmic reticulum stress pathway  and ciliary neurotrophic factor (CNTF) to induce the astrocytic lineage. Early methods were capable of generating iPSC-derived cells that expressed a relatively high level of astrocyte markers  and exhibited functional characteristics of astrocytes such as spontaneous calcium transients, ability to uptake glutamate, and stimulation-dependent cytokine secretion . HoweverS100ß was found to be upregulated in T21 astrocyte-like cells and modulation of S100ß levels was able to restore specific phenotypes including elevated reactive oxygen species and abnormal calcium signaling , neurotrophin 3 (NT3), triiodo-L-thyronine (T3), insulin-like growth factor 1 (IGF-1), and hepatocyte growth factor (HGF) to generate oligodendrocyte progenitor cells (OPCs) . Similar+ progenitors and reduced NKX2.2+ cells  . These pnditions . Since tgnatures . Injectignatures   that occur in disorders such as DS, they fail to capture a complete picture of the cell-cell interactions that occur in the brain environment throughout the course of neurological disease. To overcome these limitations, more complex models of the brain are in development, including cerebral and brain-region specific organoids as well as human-mouse chimeras.Cerebral organoids were first described a decade ago that took advantage of the propensity of human pluripotent stem cells grown in suspension aggregates to preferentially differentiate into neuroectoderm in the absence of patterning factors . This meThe majority of brain organoid studies utilize methods that mimic the composition of the dorsal forebrain, resulting in ventricular-like neural rosette structures that differentiate into neurons and recapitulate the inside-out migration of the six-layered cerebral cortex. However, as oligodendrocytes and interneurons primarily originate from the ventral forebrain, their numbers are limited in these models. Activation of SHH signaling can induce ventralization of NPCs and organoids  and incoIn the context of DS, several brain region-specific organoids are of interest to gain insights into the regional vulnerability of the disorder including dorsal and ventral forebrain, hippocampal, retinal, and cerebellar organoids. Cerebral organoids generated from DS iPSCs display pathological AD hallmarks including elevated amyloid-ß and hyperphosphorylated tau  Table 1Table 1. + progenitor cells, which specify GABAergic interneuron fate, are elevated in frequency in T21 organoids. This increase in fate-restricted progenitors was correlated with an increased frequency of specific interneuron subtypes including calretinin- (CR), somatostatin- (SST), and GAD65/67-expressing cells in both ventralized organoids and postmortem DS brain tissue  has proven challenging to recapitulate in 3D cultures, but this type of system could provide significant insights into the cerebrovasculature changes observed in DS . The BBBom iPSCs  and protom iPSCs . Advanceom iPSCs  and syntom iPSCs  have sucrganoids . While t−/− or Rag2−/−) are used to prevent host rejection of the graft, and in some cases, such as for microglia differentiation, additional human transgenes are necessary to support survival and differentiation of the human cells  have successfully generated human-mouse chimeras engrafted with cortical excitatory neurons (in vivo imaging showed increased synaptic stability and altered neural population activity as measured by calcium imaging in DS cortical neurons (+NKX2.1+ NPCs, into the cortex of neonatal pups and recapitulated in vitro findings of increased production of GABAergic neurons (Studies utilizing xenotransplantation of DS iPSC-derived brain cells into immunodeficient mice (Rag1 neurons , GABAerg neurons , microgl neurons  (reviewe neurons  (Table 1 neurons . Transpl neurons , consist neurons . Neurona neurons . Huo et  neurons . Mice en neurons . It rema−/− immunocompromised mouse strain (Collectively, the chimeric system enables detailed study of the cell autonomous consequences of T21 on human brain cell types in a living organism as well as behavioral read-outs of cell type-specific consequences of T21. To properly interpret rodent behavioral assays, it is critical to first assess the overall health of the animal. Compromised vision has been reported in the Rag2e strain , suggeste strain  or genete strain  means, ie strain . It is ae strain .in vitro organoids such as increased growth, higher synaptic density, elevated neuronal activity, and a slightly more advanced transcriptional signature (More recently, groups have transplanted whole organoids into the early postnatal rodent brain and observed functional integration into relevant neural circuits . Transplignature . ImportaThe brain is one of the most impacted organs in response to trisomy 21 and neurological dysfunction is a primary contributing factor to reduced quality of life in individuals with DS. Human postmortem studies have indicated some consistent clinical features of the DS brain, including reduced volume, dysfunctions in NPC proliferation and differentiation, altered neuronal connectivity and communication, and neuroinflammation. Some of these features have been successfully modeled using rodents, however, species-specific differences in brain development and maturation preclude our ability to fully model neurological disorders like DS and hinder the development of effective therapeutics.in vivo conditions and model neurological diseases such as DS and DS-AD will certainly improve.It has been 15 years since the generation of iPSCs from individuals with DS, which were among the first disease-associated iPSC lines to be reported . Since tTo date, DS iPSC-derived brain cell types have recapitulated NPC dysfunctions including altered proliferation and differentiation, implicating key signaling pathways such as WNT  and SHH in vivo over the lifespan and in disease that will undoubtedly serve as a reference to facilitate generation of these cell states in vitro and refinement of culture systems to study the cellular and molecular mechanisms underlying neurological disorders such as DS.While significant advances have been made in 3D cell culture techniques, these systems are still unable to fully recapitulate the cellular diversity, developmental niches, and regional structures that exist in the brain. For instance, while protocols exist to generate hippocampal organoids, they lack formation of the neurogenic niche thus hindering adult neurogenesis studies in this system. Further, there is a growing appreciation for the enormous cellular diversity that exists in the brain, first described in Ramon y Cajal’s seminal work . Single-