With advances in connectomics, transcriptome and neurophysiological technologies, the neuroscience of brain-wide neural circuits is poised to take off. A major challenge is to understand how a vast ...diversity of functions is subserved by parcellated areas of mammalian neocortex composed of repetitions of a canonical local circuit. Areas of the cerebral cortex differ from each other not only in their input-output patterns but also in their biological properties. Recent experimental and theoretical work has revealed that such variations are not random heterogeneities; rather, synaptic excitation and inhibition display systematic macroscopic gradients across the entire cortex, and they are abnormal in mental illness. Quantitative differences along these gradients can lead to qualitatively novel behaviours in non-linear neural dynamical systems, by virtue of a phenomenon mathematically described as bifurcation. The combination of macroscopic gradients and bifurcations, in tandem with biological evolution, development and plasticity, provides a generative mechanism for functional diversity among cortical areas, as a general principle of large-scale cortical organization.
Currently, there is no strong evidence of the well-established biomarkers for immune checkpoint inhibitors (ICIs) in nasopharyngeal carcinoma (NPC). Here, we aimed to reveal the heterogeneity of ...tumour microenvironment (TME) through virtual microdissection of gene expression profiles. An immune-enriched subtype was identified in 38% (43/113) of patients, which was characterized by significant enrichment of immune cells or immune responses. The remaining patients were therefore classified as a non-Immune Subtype (non-IS), which exhibited highly proliferative features. Then we identified a tumour immune evasion state within the immune-enriched subtype (18/43, 42%), in which high expression of exclusion- and dysfunction-related signatures was observed. These subgroups were designated the Evaded and Active Immune Subtype (E-IS and A-IS), respectively. We further demonstrated that A-IS predicted favourable survival and improved ICI response as compared to E-IS and non-IS. In summary, this study introduces the novel immune subtypes and demonstrates their feasibility in tailoring immunotherapeutic strategies.
Artificial neural networks (ANNs) are essential tools in machine learning that have drawn increasing attention in neuroscience. Besides offering powerful techniques for data analysis, ANNs provide a ...new approach for neuroscientists to build models for complex behaviors, heterogeneous neural activity, and circuit connectivity, as well as to explore optimization in neural systems, in ways that traditional models are not designed for. In this pedagogical Primer, we introduce ANNs and demonstrate how they have been fruitfully deployed to study neuroscientific questions. We first discuss basic concepts and methods of ANNs. Then, with a focus on bringing this mathematical framework closer to neurobiology, we detail how to customize the analysis, structure, and learning of ANNs to better address a wide range of challenges in brain research. To help readers garner hands-on experience, this Primer is accompanied with tutorial-style code in PyTorch and Jupyter Notebook, covering major topics.
Artificial neural networks (ANNs) are essential tools in modern machine learning. In this Primer, Yang and Wang introduce how new computational models based on ANNs can be built, analyzed, and customized to study a wide range of neuroscientific questions.
With dramatic changes in lifestyles over the last 20 years, nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver disorder in China but has not received sufficient attention. ...NAFLD‐related advanced liver disease and its mortality along with its overall disease burden are expected to increase substantially. There is thus an imperative need to clarify the epidemiological features of NAFLD to guide a holistic approach to management. We summarize eight epidemiological features of NAFLD in China over the past two decades using systematic review and meta‐analysis methodology. Our data reveal a rapid growth in the NAFLD population, especially among younger individuals. Importantly, there is a strong ethnic difference in body mass index (BMI) and genetic risk of NAFLD compared with the US population. The etiology of advanced liver disease and its complications (e.g., hepatocellular carcinoma) has been altered because of a Westernized lifestyle and the implementation of effective vaccination strategies against viral hepatitis. Regional epidemiological patterns of NAFLD indicate that economics, environment, and lifestyle are critical factors in disease progression. The analysis also indicates that a large number of patients remain undiagnosed and untreated because of the inadequacy of diagnostic tools and the absence of effective pharmacologic therapies. Given the burden of NAFLD, future policy and research efforts need to address knowledge gaps to mitigate the risk burden.
Synchronous rhythms represent a core mechanism for sculpting temporal coordination of neural activity in the brain-wide network. This review focuses on oscillations in the cerebral cortex that occur ...during cognition, in alert behaving conditions. Over the last two decades, experimental and modeling work has made great strides in elucidating the detailed cellular and circuit basis of these rhythms, particularly gamma and theta rhythms. The underlying physiological mechanisms are diverse (ranging from resonance and pacemaker properties of single cells to multiple scenarios for population synchronization and wave propagation), but also exhibit unifying principles. A major conceptual advance was the realization that synaptic inhibition plays a fundamental role in rhythmogenesis, either in an interneuronal network or in a reciprocal excitatory-inhibitory loop. Computational functions of synchronous oscillations in cognition are still a matter of debate among systems neuroscientists, in part because the notion of regular oscillation seems to contradict the common observation that spiking discharges of individual neurons in the cortex are highly stochastic and far from being clocklike. However, recent findings have led to a framework that goes beyond the conventional theory of coupled oscillators and reconciles the apparent dichotomy between irregular single neuron activity and field potential oscillations. From this perspective, a plethora of studies will be reviewed on the involvement of long-distance neuronal coherence in cognitive functions such as multisensory integration, working memory, and selective attention. Finally, implications of abnormal neural synchronization are discussed as they relate to mental disorders like schizophrenia and autism.
With rapid lifestyle transitions, the increasing burden of nonalcoholic fatty liver disease (NAFLD) in China has emerged as a major public health issue. To obtain a comprehensive overview of the ...status of NAFLD over the past decade, we evaluated the epidemiology, risk factors, complications, and management of NAFLD in China through a systematic review and meta‐analysis. Five English literature databases and three Chinese databases were searched for relevant topics from 2008 to 2018. A total of 392 studies with a population of 2,054,554 were included. National prevalence of NAFLD was 29.2%, with a heavier disease burden among the middle‐aged, males, those in northwest China and Taiwan, regions with a gross domestic product per capita greater than 100,000 yuan, and Uygur and Hui ethnic groups. Currently, original studies on natural history and complications of NAFLD in China are scarce. Several studies revealed that NAFLD is positively correlated with the incidence of extrahepatic tumors, diabetes, cardiovascular disease and metabolic syndrome. The Chinese population may have a higher hereditary risk of NAFLD due to more frequent nonsynonymous mutations in genes regulating lipid metabolism. Ultrasonography is the primary imaging tool in the detection of NAFLD in China. Serum tests and risk stratification algorithms for staging NAFLD remain under investigation. Specific pharmaceutical treatments for NAFLD are still undergoing clinical trials. It is noteworthy that the Chinese are underrepresented compared with their proportion of the NAFLD population in such trials. Conclusion: China experienced an unexpected rapid increase in the burden of NAFLD over a short period. Rising awareness and urgent actions need to be taken in order to control the NAFLD pandemic in China.
In recent years, the research on fluorescent probes has developed rapidly. Coumarin fluorescent probes have also been one of the hot topics in recent years. For the synthesis and application of ...coumarin fluorescent probes, great progress has been made. Coumarin fluorescent probes have become more and more widely used in biochemistry, environmental protection, and disease prevention, and have broad prospects. This review introduces the three main light emitting mechanisms (PET, ICT, FRET) of fluorescent probes, and enumerates some probes based on this light emitting mechanism. In terms of the synthesis of coumarin fluorescent probes, the existing substituents on the core of coumarin compounds were modified. Based on the positions of the modified substituents, some of the fluorescent probes reported in the past ten years are listed. Most of the fluorescent probes are formed by modifying the 3 and 7 position substituents on the mother nucleus, and the 4 and 8 position substituents are relatively less modified. In terms of probe applications, the detection and application of coumarin fluorescent probes for Cu
2+
, Hg
2+
, Mg
2+
, Zn
2+
, pH, environmental polarity, and active oxygen and sulfide in the past ten years are mainly introduced.
In recent years, the research on fluorescent probes has developed rapidly.
Computational modeling of brain mechanisms of cognition has largely focused on the cortex, but recent experiments have shown that higher-order nuclei of the thalamus participate in major cognitive ...functions and are implicated in psychiatric disorders. Here, we show that a pulvino-cortical circuit model, composed of the pulvinar and two cortical areas, captures several physiological and behavioral observations related to the macaque pulvinar. Effective connections between the two cortical areas are gated by the pulvinar, allowing the pulvinar to shift the operation regime of these areas during attentional processing and working memory and resolve conflict in decision making. Furthermore, cortico-pulvinar projections that engage the thalamic reticular nucleus enable the pulvinar to estimate decision confidence. Finally, feedforward and feedback pulvino-cortical pathways participate in frequency-dependent inter-areal interactions that modify the relative hierarchical positions of cortical areas. Overall, our model suggests that the pulvinar provides crucial contextual modulation to cortical computations associated with cognition.
•Pulvino-cortical pathways modulate attention, working memory, and decision making•The pulvinar controls the effective connectivity within and across cortical areas•A plastic cortico-TRN-pulvinar circuit can estimate decision confidence•The pulvinar can regulate frequency-dependent and hierarchical cortical interactions
Very little is known about the function of the thalamus beyond relaying sensory information to the cortex. Jaramillo et al. present a biologically based model of pulvino-cortical interactions and provide a unified account of the pulvinar’s computational role across cognitive tasks.
Long noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) ...progression and could be a potential therapeutic target.
We screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact with LINRIS (Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells with LINRIS inhibited were tested in vitro and in vivo.
LINRIS was upregulated in CRC tissues from patients with poor overall survival (OS), and LINRIS inhibition led to the impaired CRC cell line growth. Moreover, knockdown of LINRIS resulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N
-methyladenosine (m
A) 'reader'. LINRIS blocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown of LINRIS attenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription of LINRIS could be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition of LINRIS suppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models.
LINRIS is an independent prognostic biomarker for CRC. The LINRIS-IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.
Oxygen‐redox of layer‐structured metal‐oxide cathodes has drawn great attention as an effective approach to break through the bottleneck of their capacity limit. However, reversible oxygen‐redox can ...only be obtained in the high‐voltage region (usually over 3.5 V) in current metal‐oxide cathodes. Here, we realize reversible oxygen‐redox in a wide voltage range of 1.5–4.5 V in a P2‐layered Na0.7Mg0.2Fe0.2Mn0.6□0.2O2 cathode material, where intrinsic vacancies are located in transition‐metal (TM) sites and Mg‐ions are located in Na sites. Mg‐ions in the Na layer serve as “pillars” to stabilize the layered structure during electrochemical cycling, especially in the high‐voltage region. Intrinsic vacancies in the TM layer create the local configurations of “□–O–□”, “Na–O–□” and “Mg–O–□” to trigger oxygen‐redox in the whole voltage range of charge–discharge. Time‐resolved techniques demonstrate that the P2 phase is well maintained in a wide potential window range of 1.5–4.5 V even at 10 C. It is revealed that charge compensation from Mn‐ and O‐ions contributes to the whole voltage range of 1.5–4.5 V, while the redox of Fe‐ions only contributes to the high‐voltage region of 3.0–4.5 V. The orphaned electrons in the nonbonding 2p orbitals of O that point toward TM‐vacancy sites are responsible for reversible oxygen‐redox, and Mg‐ions in Na sites suppress oxygen release effectively.
Na0.7Mg0.2Fe0.2Mn0.6□0.2O2 with native transitional metal (TM) vacancies is designed as a novel cathode material for sodium‐ion batteries. The TM vacancies lead to nonbonding O 2p orbitals in this material, pointing toward these vacancies triggering reversible whole‐voltage‐range oxygen redox during charge and discharge processes. This work provides new ideals for design of cathode materials in anionic redox chemistry.
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