Skilful nowcasting of extreme precipitation with NowcastNet.

Extreme precipitation is a considerable contributor to meteorological disasters and there is a great need to mitigate its socioeconomic effects through skilful nowcasting that has high resolution, long lead times and local details1-3. Current methods are subject to blur, dissipation, intensity or location errors, with physics-based numerical methods struggling to capture pivotal chaotic dynamics such as convective initiation4 and data-driven learning methods failing to obey intrinsic physical laws such as advective conservation5. We present NowcastNet, a nonlinear nowcasting model for extreme precipitation that unifies physical-evolution schemes and conditional-learning methods into a neural-network framework with end-to-end forecast error optimization. On the basis of radar observations from the USA and China, our model produces physically plausible precipitation nowcasts with sharp multiscale patterns over regions of 2,048 km × 2,048 km and with lead times of up to 3 h. In a systematic evaluation by 62 professional meteorologists from across China, our model ranks first in 71% of cases against the leading methods. NowcastNet provides skilful forecasts at light-to-heavy rain rates, particularly for extreme-precipitation events accompanied by advective or convective processes that were previously considered intractable.

Up-regulated novel-miR-17 promotes hypothermic reperfusion arrhythmias by negatively targeting Gja1 and mediating activation of the PKC/c-Jun signaling pathway.

BACKGROUND: Hypothermic ischemia-reperfusion arrhythmia is a common complication of cardiothoracic surgery under cardiopulmonary bypass, but few studies have focused on this type of arrhythmia. Our prior study discovered reduced myocardial Cx43 protein levels may be linked to hypothermic reperfusion arrhythmias. However, more detailed molecular mechanism research is required. METHOD: The microRNA and mRNA expression levels in myocardial tissues were detected by real-time quantitative PCR (RT-qPCR). Besides, the occurrence of hypothermic reperfusion arrhythmias and changes in myocardial electrical conduction were assessed by electrocardiography and ventricular epicardial activation mapping. Furthermore, bioinformatics analysis, applying antagonists of miRNA, western blotting, immunohistochemistry, a dual luciferase assay, and pearson correlation analysis were performed to investigate the underlying molecular mechanisms. RESULTS: The expression level of novel-miR-17 was up-regulated in hypothermic ischemia-reperfusion myocardial tissues. Inhibition of novel-miR-17 upregulation ameliorated cardiomyocyte edema, reduced apoptosis, increased myocardial electrical conduction velocity, and shortened the duration of reperfusion arrhythmias. Mechanistic studies showed that novel-miR-17 reduced the expression of Cx43 by directly targeting Gja1 while mediating the activation of the PKC/c-Jun signaling pathway. CONCLUSION: Up-regulated novel-miR-17 is a newly discovered pro-arrhythmic microRNA that may serve as a potential therapeutic target and biomarker for hypothermic reperfusion arrhythmias.

Phase-Change Based Oxygen Carriers Improve Acute Cerebral Hypoxia.

Stroke is the second leading cause of death worldwide, and hypoxia is a major crisis of the brain after stroke. Therefore, providing oxygen to the brain microenvironment can effectively protect neurons from damage caused by cerebral hypoxia. However, there is a lack of timely and effective means of oxygen delivery clinically to the brain for acute cerebral hypoxia. Here, a phase-change based nano oxygen carrier is reported, which can undergo a phase change in response to increasing temperature in the brain, leading to oxygen release. The nano oxygen carrier demonstrate intracerebral oxygen delivery capacity and is able to release oxygen in the hypoxic and inflammatory region of the brain. In the acute ischemic stroke mouse model, the nano oxygen carrier can effectively reduce the area of cerebral infarction and decrease the level of inflammation triggered by cerebral hypoxia. By taking advantage of the increase in temperature during cerebral hypoxia, phase-change oxygen carrier proposes a new intracerebral oxygen delivery strategy for reducing acute cerebral hypoxia.

Autophagy-modulating biomaterials: multifunctional weapons to promote tissue regeneration.

Autophagy is a self-renewal mechanism that maintains homeostasis and can promote tissue regeneration by regulating inflammation, reducing oxidative stress and promoting cell differentiation. The interaction between biomaterials and tissue cells significantly affects biomaterial-tissue integration and tissue regeneration. In recent years, it has been found that biomaterials can affect various processes related to tissue regeneration by regulating autophagy. The utilization of biomaterials in a controlled environment has become a prominent approach for enhancing the tissue regeneration capabilities. This involves the regulation of autophagy in diverse cell types implicated in tissue regeneration, encompassing the modulation of inflammatory responses, oxidative stress, cell differentiation, proliferation, migration, apoptosis, and extracellular matrix formation. In addition, biomaterials possess the potential to serve as carriers for drug delivery, enabling the regulation of autophagy by either activating or inhibiting its processes. This review summarizes the relationship between autophagy and tissue regeneration and discusses the role of biomaterial-based autophagy in tissue regeneration. In addition, recent advanced technologies used to design autophagy-modulating biomaterials are summarized, and rational design of biomaterials for providing controlled autophagy regulation via modification of the chemistry and surface of biomaterials and incorporation of cells and molecules is discussed. A better understanding of biomaterial-based autophagy and tissue regeneration, as well as the underlying molecular mechanisms, may lead to new possibilities for promoting tissue regeneration. Video Abstract.

The Function of Circular RNAs in Myocardial Ischemia-Reperfusion Injury: Underlying Mechanisms and Therapeutic Advancement.

Myocardial ischemia reperfusion injury (MIRI) represents a prevalent and severe cardiovascular condition that arises primarily after myocardial infarction recanalization, cardiopulmonary bypass surgery, and both stable and unstable angina pectoris. MIRI can induce malignant arrhythmias and heart failure, thereby increasing the morbidity and mortality rates associated with cardiovascular diseases. Hence, it is important to assess the potential pathological mechanisms of MIRI and develop effective treatments. The role of circular RNAs (circRNAs) in MIRI has increasingly become a topic of interest in recent years. Moreover, significant evidence suggests that circRNAs play a critical role in MIRI pathogenesis, thereby representing a promising therapeutic target. This review aimed to provide a comprehensive overview of the current understanding of the role of circRNAs in MIRI and discuss the mechanisms through which circRNAs contribute to MIRI development and progression, including their effects on apoptosis, inflammation, oxidative stress, and autophagy. Furthermore, the potential therapeutic applications of circRNAs in MIRI treatment, including the use of circRNA-based therapies and modulation of circRNA expression levels, have been explored. Overall, this paper highlights the importance of circRNAs in MIRI and underscores their potential as novel therapeutic targets.

Two-Dimensional Reconfigurable Non-Hermitian Gauged Laser Array.

Topological effects in photonic non-Hermitian systems have recently led to extraordinary discoveries including nonreciprocal lasing, topological insulator lasers, and topological metamaterials, to mention a few. These effects, although realized in non-Hermitian systems, are all stemming from their Hermitian components. Here we experimentally demonstrate the topological skin effect and boundary sensitivity, induced by the imaginary gauge field in a two-dimensional laser array, which are fundamentally different from any Hermitian topological effects and intrinsic to open systems. By selectively and asymmetrically injecting gain into the system, we have synthesized an imaginary gauge field on chip, which can be flexibly reconfigured on demand. We show not only that the non-Hermitian topological features remain intact in a nonlinear nonequilibrium system, but also that they can be harnessed to enable persistent phase locking with intensity morphing. Our work lays the foundation for a dynamically reconfigurable on-chip coherent system with robust scalability, attractive for building high-brightness sources with arbitrary intensity profiles.

Research Progress in Oxygen Carrier Design and Application.

Ischemia or hypoxia can lead to pathological changes in the metabolism and function of tissues and then lead to various diseases. Timely and effective blood resuscitation or improvement of hypoxia is very important for the treatment of diseases. However, there is a need to develop stable, nontoxic, and immunologically inert oxygen carriers due to limitations such as blood shortages, different blood types, and the risk of transmitting infections. With the development of various technologies, oxygen carriers based on hemoglobin and perfluorocarbon have been widely studied in recent years. This paper reviews the development and application of hemoglobin and perfluorocarbon oxygen carriers. The design of oxygen carriers was analyzed, and their application as blood substitutes or oxygen carriers in various hypoxic diseases was discussed. Finally, the characteristics and future research of ideal oxygen carriers were prospected to provide reference for follow-up research.

PDHA1 Alleviates Myocardial Ischemia-Reperfusion Injury by Improving Myocardial Insulin Resistance During Cardiopulmonary Bypass Surgery in Rats.

OBJECTIVE: Cardiopulmonary bypass (CPB) is a requisite technique for thoracotomy in advanced cardiovascular surgery. However, the consequent myocardial ischemia-reperfusion injury (MIRI) is the primary culprit behind cardiac dysfunction and fatal consequences post-operation. Prior research has posited that myocardial insulin resistance (IR) plays a vital role in exacerbating the progression of MIRI. Nonetheless, the exact mechanisms underlying this phenomenon remain obscure. METHODS: We constructed pyruvate dehydrogenase E1 α subunit (PDHA1) interference and overexpression rats and used ascending aorta occlusion in an in vivo model of CPB-MIRI. We devised an in vivo model of CPB-MIRI by constructing rat models with both pyruvate dehydrogenase E1α subunit (PDHA1) interference and overexpression through ascending aorta occlusion. We analyzed myocardial glucose metabolism and the degree of myocardial injury using functional monitoring, biochemical assays, and histological analysis. RESULTS: We discovered a clear downregulation of glucose transporter 4 (GLUT4) protein content expression in the CPB I/R model. In particular, cardiac-specific PDHA1 interference resulted in exacerbated cardiac dysfunction, significantly increased myocardial infarction area, more pronounced myocardial edema, and markedly increased cardiomyocyte apoptosis. Notably, the opposite effect was observed with PDHA1 overexpression, leading to a mitigated cardiac dysfunction and decreased incidence of myocardial infarction post-global ischemia. Mechanistically, PDHA1 plays a crucial role in regulating the protein content expression of GLUT4 on cardiomyocytes, thereby controlling the uptake and utilization of myocardial glucose, influencing the development of myocardial insulin resistance, and ultimately modulating MIRI. CONCLUSION: Overall, our study sheds new light on the pivotal role of PDHA1 in glucose metabolism and the development of myocardial insulin resistance. Our findings hold promising therapeutic potential for addressing the deleterious effects of MIRI in patients.

Insulin reduces pyroptosis-induced inflammation by PDHA1 dephosphorylation-mediated NLRP3 activation during myocardial ischemia-reperfusion injury.

BACKGROUND: Previous studies proved that pyrin domain-containing protein 3 (NLRP3)-induced pyroptosis plays an important role in Myocardial ischemia-reperfusion injury (MIRI). Insulin can inhibit the activation of NLRP3 inflammasome, although the exact mechanism remains unclear. The aim of this study was to determine whether insulin reduces NLRP3-induced pyroptosis by regulating pyruvate dehydrogenase E1alpha subunit (PDHA1) dephosphorylation during MIRI. METHODS: Rat hearts were subject to 30 min global ischemia followed by 60 min reperfusion, with or without 0.5 IU/L insulin. Myocardial ischemia-reperfusion injury was evaluated by measuring myocardial enzymes release, Cardiac hemodynamics, pathological changes, infarct size, and apoptosis rate. Cardiac aerobic glycolysis was evaluated by measuring ATP, lactic acid content, and pyruvate dehydrogenase complex (PDHc) activity in myocardial tissue. Recombinant adenoviral vectors for PDHA1 knockdown were constructed. Pyroptosis-related proteins were measured by Western blotting analysis, immunohistochemistry staining, and ELISA assay, respectively. RESULTS: It was found that insulin significantly reduced the area of myocardial infarction, apoptosis rate, and improved cardiac hemodynamics, pathological changes, energy metabolism. Insulin inhibits pyroptosis-induced inflammation during MIRI. Subsequently, Adeno-associated virus was used to knock down cardiac PDHA1 expression. Knockdown PDHA1 not only promoted the expression of NLRP3 but also blocked the inhibitory effect of insulin on NLRP3-mediated pyroptosis in MIRI. CONCLUSIONS: Results suggest that insulin protects against MIRI by regulating PDHA1 dephosphorylation, its mechanism is not only to improve myocardial energy metabolism but also to reduce the NLRP3-induced pyroptosis.

Protective Effects of Jujubosides on 6-OHDA-Induced Neurotoxicity in SH-SY5Y and SK-N-SH Cells.

6-hydroxydopamine (6-OHDA) is used to induce oxidative damage in neuronal cells, which can serve as an experimental model of Parkinson's disease (PD). Jujuboside A and B confer free radical scavenging effects but have never been examined for their neuroprotective effects, especially in PD; therefore, in this study, we aimed to investigate the feasibility of jujubosides as protectors of neurons against 6-OHDA and the underlying mechanisms. 6-OHDA-induced neurotoxicity in the human neuronal cell lines SH-SY5Y and SK-N-SH, was used to evaluate the protective effects of jujubosides. These findings indicated that jujuboside A and B were both capable of rescuing the 6-OHDA-induced loss of cell viability, activation of apoptosis, elevation of reactive oxygen species, and downregulation of the expression levels of superoxide dismutase, catalase, and glutathione peroxidase. In addition, jujuboside A and B can reverse a 6-OHDA-elevated Bax/Bcl-2 ratio, downregulate phosphorylated PI3K and AKT, and activate caspase-3, -7, and -9. These findings showed that jujubosides were capable of protecting both SH-SY5Y and SK-N-SH neuronal cells from 6-OHDA-induced toxicity via the rebalancing of the redox system, together with the resetting of the PI3K/AKT apoptotic signaling cascade. In conclusion, jujuboside may be a potential drug for PD prevention.

The burden of being certain: National identity certainty predicts support for COVID-Related restrictive measures and outgroup conspiracy beliefs.

In dealing with the COVID-19 pandemic, government officials often encounter two concurrent concerns: they have to enforce necessary public health and safety measures to manage COVID-19. Meanwhile, they also have to mitigate conspiracy beliefs about COVID-19. To shed light on these issues, we conducted two studies to investigate national identity certainty (i.e., the extent to which people are certain about their national identity) as a predictor of (a) support for restrictive measures to curtail COVID-19 and (b) conspiracy beliefs about an outgroup as the culprit of COVID-19. Study 1 was a three-week longitudinal study (N = 301) where we investigated the relationships both on a between-person level (differences between individuals) and on a within-person level (week-by-week fluctuations of the same individual). We found that individual differences in national identity certainty predicted increased support for restrictive measures and increased outgroup conspiracy beliefs. These relationships emerged, even when we controlled for national identity positivity, that is, the extent to which people see their national identity in positive light. In Study 2 (N = 316), we used a cross-sectional correlational design and replicated the findings of Study 1. Moreover, we found that the relationships were explained by distinct threat perceptions: realistic threat explained the increased support for restrictive measures, whereas symbolic threat explained the increased outgroup conspiracy beliefs. Overall, our findings suggest that support for restrictive measures and outgroup conspiracy beliefs can be seen as attempts of people high in national identity certainty to address the distinct threats of COVID-19.

Improved seagull optimization algorithm of partition and XGBoost of prediction for fuzzy time series forecasting of COVID-19 daily confirmed.

The establishment of fuzzy relations and the fuzzification of time series are the top priorities of the model for predicting fuzzy time series. A lot of literature studied these two aspects to ameliorate the capability of the forecasting model. In this paper, we proposed a new method(FTSOAX) to forecast fuzzy time series derived from the improved seagull optimization algorithm(ISOA) and XGBoost. For increasing the accurateness of the forecasting model in fuzzy time series, ISOA is applied to partition the domain of discourse to get more suitable intervals. We improved the seagull optimization algorithm(SOA) with the help of the Powell algorithm and a random curve action to make SOA have better convergence ability. Using XGBoost to forecast the change of fuzzy membership in order to overcome the disadvantage that fuzzy relation leads to low accuracy. We obtained daily confirmed COVID-19 cases in 7 countries as a dataset to demonstrate the performance of FTSOAX. The results show that FTSOAX is superior to other fuzzy forecasting models in the application of prediction of COVID-19 daily confirmed cases.

Monitoring Mitophagy via the FRET Mechanism: Visualizing Mitochondria, Lysosomes, and Autolysosomes in Three Different Sets of Fluorescence Signals.

Mitophagy is a vital biological process playing central roles in the regulation of metabolic activity and quality control of mitochondria. The presented dual-color fluorescent probes to directly monitor mitophagy were based on the optical response to pH change during mitophagy, but pH fluctuation may lead to interference. To overcome this, herein, two fluorescent probes (G-Mito, R-Lyso) were rationally designed to visualize mitophagy directly in a dual-color manner, relying on the Förster resonance energy transfer (FRET) process for the first time. Green emissive G-Mito targeted and anchored the mitochondria via reaction with protein thiols. Red-emissive R-Lyso exclusively targeted lysosomes. Live cells loaded with the two probes demonstrated strong fluorescence in only the green channel with excitation at 405 nm. After mitophagy, G-Mito in mitochondria was delivered into the lysosomes, and red fluorescence evidently increased due to the FRET process. With the probes, mitochondria, lysosomes, and autolysosomes could be discriminatively visualized in three different sets of signals. Mitophagy induced by starvation and in normal physiological status were successfully observed. The probes revealed that a certain amount of H2O2 could induce mitophagy. We expect that the two probes can serve as molecular tools for validation of mitophagy and promote the development of related areas.

Matrix metalloproteinase inhibitors enhance the efficacy of frontline drugs against Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) remains a grave threat to world health with emerging drug resistant strains. One prominent feature of Mtb infection is the extensive reprogramming of host tissue at the site of infection. Here we report that inhibition of matrix metalloproteinase (MMP) activity by a panel of small molecule inhibitors enhances the in vivo potency of the frontline TB drugs isoniazid (INH) and rifampicin (RIF). Inhibition of MMP activity leads to an increase in pericyte-covered blood vessel numbers and appears to stabilize the integrity of the infected lung tissue. In treated mice, we observe an increased delivery and/or retention of frontline TB drugs in the infected lungs, resulting in enhanced drug efficacy. These findings indicate that targeting Mtb-induced host tissue remodeling can increase therapeutic efficacy and could enhance the effectiveness of current drug regimens.

Development of a precision medicine pipeline to identify personalized treatments for colorectal cancer.

BACKGROUND: Metastatic colorectal cancer (CRC) continues to be a major health problem, and current treatments are primarily for disease control and palliation of symptoms. In this study, we developed a precision medicine strategy to discover novel therapeutics for patients with CRC. METHODS: Six matched low-passage cell lines and patient-derived xenografts (PDX) were established from CRC patients undergoing resection of their cancer. High-throughput drug screens using a 119 FDA-approved oncology drug library were performed on these cell lines, which were then validated in vivo in matched PDXs. RNA-Seq analysis was then performed to identify predictors of response. RESULTS: Our study revealed marked differences in response to standard-of-care agents across patients and pinpointed druggable pathways to treat CRC. Among these pathways co-targeting of fibroblast growth factor receptor (FGFR), SRC, platelet derived growth factor receptor (PDGFR), or vascular endothelial growth factor receptor (VEGFR) signaling was found to be an effective strategy. Molecular analyses revealed potential predictors of response to these druggable pathways. CONCLUSIONS: Our data suggests that the use of matched low-passage cell lines and PDXs is a promising strategy to identify new therapies and pathways to treat metastatic CRC.

Protective effects of valproic acid on 6-hydroxydopamine-induced neuroinjury.

Oxidative stress may play critically important roles in the etiology of Parkinson's disease (PD). 6-Hydroxydopamine (6-OHDA) is a physiological neurotoxin reported to induce oxidative-induced apoptosis of dopaminergic neurons in PD mice models. Valproic acid (VPA), a clinical mood stabilizer, is a HDAC inhibitor with neuroprotective capacities. In the study, we aim at examining the feasibility of VPA as a protector for dopaminergic neurons against damage from 6-OHDA, and the intracellular mechanisms. The 6-OHDA-induced neurotoxicity to the human dopaminergic cell line SH-SY5Y was applied for examining VPA protective effects. Pretreatment with VPA was able to improve cell viability and reduce 6-OHDA-induced reactive oxygen species. Furthermore, a significant suppression of apoptotic caspases including cleaved caspase-3, caspase-7, and caspase-9 was observed. The results also revealed VPA decreased the 6-OHDA-induced Bax/Bcl2 ratio, as measured at protein level. These novel findings indicate that VPA may be capable of protecting the SH-SY5Y dopaminergic neuronal cells from 6-OHDA-induced toxicity via the deceasing of apoptotic caspases (cleaved caspase-3, caspase-7, and caspase-9) and reducing of the Bax/Bcl2 ratio. Very possibly, VPA could serve as not only a mood stabilizer but also a potential antidote for PD prevention.

An Efficient Alert Aggregation Method Based on Conditional Rough Entropy and Knowledge Granularity.

With the emergence of network security issues, various security devices that generate a large number of logs and alerts are widely used. This paper proposes an alert aggregation scheme that is based on conditional rough entropy and knowledge granularity to solve the problem of repetitive and redundant alert information in network security devices. Firstly, we use conditional rough entropy and knowledge granularity to determine the attribute weights. This method can determine the different important attributes and their weights for different types of attacks. We can calculate the similarity value of two alerts by weighting based on the results of attribute weighting. Subsequently, the sliding time window method is used to aggregate the alerts whose similarity value is larger than a threshold, which is set to reduce the redundant alerts. Finally, the proposed scheme is applied to the CIC-IDS 2018 dataset and the DARPA 98 dataset. The experimental results show that this method can effectively reduce the redundant alerts and improve the efficiency of data processing, thus providing accurate and concise data for the next stage of alert fusion and analysis.

Fucosylation Deficiency in Mice Leads to Colitis and Adenocarcinoma.

BACKGROUND & AIMS: De novo synthesis of guanosine diphosphate (GDP)-fucose, a substrate for fucosylglycans, requires sequential reactions mediated by GDP-mannose 4,6-dehydratase (GMDS) and GDP-4-keto-6-deoxymannose 3,5-epimerase-4-reductase (FX or tissue specific transplantation antigen P35B [TSTA3]). GMDS deletions and mutations are found in 6%-13% of colorectal cancers; these mostly affect the ascending and transverse colon. We investigated whether a lack of fucosylation consequent to loss of GDP-fucose synthesis contributes to colon carcinogenesis. METHODS: FX deficiency and GMDS deletion produce the same biochemical phenotype of GDP-fucose deficiency. We studied a mouse model of fucosylation deficiency (Fx-/- mice) and mice with the full-length Fx gene (controls). Mice were placed on standard chow or fucose-containing diet (equivalent to a control fucosylglycan phenotype). Colon tissues were collected and analyzed histologically or by enzyme-linked immunosorbent assays to measure cytokine levels; T cells also were collected and analyzed. Fecal samples were analyzed by 16s ribosomal RNA sequencing. Mucosal barrier function was measured by uptake of fluorescent dextran. We transplanted bone marrow cells from Fx-/- or control mice (Ly5.2) into irradiated 8-week-old Fx-/- or control mice (Ly5.1). We performed immunohistochemical analyses for expression of Notch and the hes family bHLH transcription factor (HES1) in colon tissues from mice and a panel of 60 human colorectal cancer specimens (27 left-sided, 33 right-sided). RESULTS: Fx-/- mice developed colitis and serrated-like lesions. The intestinal pathology of Fx-/- mice was reversed by addition of fucose to the diet, which restored fucosylation via a salvage pathway. In the absence of fucosylation, dysplasia appeared and progressed to adenocarcinoma in up to 40% of mice, affecting mainly the right colon and cecum. Notch was not activated in Fx-/- mice fed standard chow, leading to decreased expression of its target Hes1. Fucosylation deficiency altered the composition of the fecal microbiota, reduced mucosal barrier function, and altered epithelial proliferation marked by Ki67. Fx-/- mice receiving control bone marrow cells had intestinal inflammation and dysplasia, and reduced expression of cytokines produced by cytotoxic T cells. Human sessile serrated adenomas and right-sided colorectal tumors with epigenetic loss of MutL homolog 1 (MLH1) had lost or had lower levels of HES1 than other colorectal tumor types or nontumor tissues. CONCLUSIONS: In mice, fucosylation deficiency leads to colitis and adenocarcinoma, loss of Notch activation, and down-regulation of Hes1. HES1 loss correlates with the development of human right-sided colorectal tumors with epigenetic loss of MLH1. These findings indicate that carcinogenesis in a subset of colon cancer is consequent to a molecular mechanism driven by fucosylation deficiency and/or HES1-loss.

A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self-renewal.

The intestinal epithelium is the fastest regenerative tissue in the body, fueled by fast-cycling stem cells. The number and identity of these dividing and migrating stem cells are maintained by a mosaic pattern at the base of the crypt. How the underlying regulatory scheme manages this dynamic stem cell niche is not entirely clear. We stimulated intestinal organoids with Notch ligands and inhibitors and discovered that intestinal stem cells employ a positive feedback mechanism via direct Notch binding to the second intron of the Notch1 gene. Inactivation of the positive feedback by CRISPR/Cas9 mutation of the binding sequence alters the mosaic stem cell niche pattern and hinders regeneration in organoids. Dynamical system analysis and agent-based multiscale stochastic modeling suggest that the positive feedback enhances the robustness of Notch-mediated niche patterning. This study highlights the importance of feedback mechanisms in spatiotemporal control of the stem cell niche.

Differential neurometabolite alterations in brains of medication-free individuals with bipolar disorder and those with unipolar depression: a two-dimensional proton magnetic resonance spectroscopy study.

OBJECTIVES: Bipolar disorder (BD) is a mental disorder characterized by periods of elevated mood and depression. Many individuals with BD are initially misdiagnosed and treated for unipolar depression (UD). In this study, we report direct comparisons between medication-free individuals with BD and those with UD in terms of the neurometabolites in the anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), parietal cortex (PC), and posterior cingulate cortex (PCC) of the brain. METHODS: Participants included medication-free patients with BD or UD, and matched healthy controls. All patients were in the depressive state and had similar symptoms. All subjects were subjected to a multi-voxel proton magnetic resonance spectroscopy procedure with a 3.0 T GE Signa MR scanner. After post-processing, the absolute concentrations of glycerophosphocholine + phosphocholine (GPC + PC), phosphocreatine + creatine (PCr + Cr), Glx (glutamate + glutamine), myo-inositol (MI), and N-acetyl aspartate (NAA) from the above brain regions were compared across the three groups. RESULTS: Patients with BD showed significantly higher levels of Glx in their ACC, lower GPC + PC, PCr + Cr, MI, and NAA in their PC, and lower NAA in their mPFC, compared to healthy controls; patients with UD presented significantly lower levels of GPC + PC, PCr + Cr, and NAA in their PCC, and lower Glx in their mPFC. All analyzed brain metabolites, except Glx, were significantly lower in the PC of patients with BD, whereas levels of GPC + PC, PCr + Cr, and NAA were significantly reduced in the PCC of patients with UD. CONCLUSIONS: These results add to the evidence of brain metabolite differences in brains of patients with UD and BD which may be of help in differentiating these two mood disorders.