SUMMARY Radial glial progenitors (RGPs) represent the major neural progenitors for generating neurons and glia in the developing mammalian cerebral cortex 1 - 3 . They position their centrosomes away from the nucleus at the ventricular zone surface 4 - 7 . However, the molecular basis and precise function of this highly unique and characteristic subcellular organization of the centrosome remain largely unknown. Here we show that apical membrane anchoring of the centrosome controls the mechanical properties of mouse cortical RGPs and consequently their mitotic behaviour and cortical size and formation. Mother centriole in RGPs specifically develops distal appendages to anchor to the apical membrane. Selective removal of Centrosomal protein 83 (CEP83) eliminates mother centriole distal appendages and disrupts centrosome apical membrane anchorage, resulting in microtubule disorganization and apical membrane stretching and stiffening. It activates mechanically-sensitive Yes-associated protein (YAP) and promotes excessive RGP proliferation and subsequent intermediate progenitor overproduction, leading to the formation of an enlarged cortex with abnormal folding. Simultaneous elimination of YAP suppresses cortical enlargement and folding caused by CEP83 removal. Together, these results uncover a previously unknown role of the centrosome in regulating the mechanical features of neural progenitors, and the size and configuration of the mammalian cerebral cortex.
Heat defense is crucial for survival and fitness. Transmission of thermosensory signals into hypothalamic thermoregulation centers represents a key layer of regulation in heat defense. Yet, how these signals are transmitted into the hypothalamus remains poorly understood. Here, we reveal that lateral parabrachial nucleus (LPB) glutamatergic prodynorphin and cholecystokinin neuron populations are progressively recruited to defend elevated body temperature. These two nonoverlapping neuron types form circuits with downstream preoptic hypothalamic neurons to inhibit the thermogenesis of brown adipose tissues (BATs) and activate tail vasodilation, respectively. Both circuits are activated by warmth and can limit fever development. The prodynorphin circuit is further required for regulating energy expenditure and body weight homeostasis. Thus, these findings establish that the genetic and functional specificity of heat defense neurons occurs as early as in the LPB and uncover categorical neuron types for encoding two heat defense variables, inhibition of BAT thermogenesis and activation of vasodilation.
ObjectiveWe systematically investigated and assessed the alterations of salivary glycopatterns and possibility as biomarkers for diagnosis of early-stage breast cancer.DesignAlterations of salivary glycopatterns were probed using lectin microarrays and blotting analysis from 337 patients with breast benign cyst or tumor (BB) or breast cancer (I/II stage) and 110 healthy humans. Their diagnostic models were constructed by a logistic stepwise regression in the retrospective cohort. Then, the performance of the diagnostic models were assessed by ROC analysis in the validation cohort. Finally, a double-blind cohort was tested to confirm the application potential of the diagnostic models.ResultsThe diagnostic models were constructed based on 9 candidate lectins (e.g., PHA-E + L, BS-I, and NPA) that exhibited significant alterations of salivary glycopatterns, which achieved better diagnostic powers with an AUC value > 0.750 (p < 0.001) for the diagnosis of BB (AUC: 0.752, sensitivity: 0.600, and specificity: 0.835) and I stage breast cancer (AUC: 0.755, sensitivity: 0.733, and specificity: 0.742) in the validation cohort. The diagnostic model of I stage breast cancer exhibited a high accuracy of 0.902 in double-blind cohort.ConclusionsThis study could contribute to the screening for patients with early-stage breast cancer based on precise alterations of salivary glycopatterns.
<p class="abstract"><strong>Background:</strong> Malnutrition is common in patients with cancer, which adversely affects the survival and quality of life of cancer patients. However, there is no national data on the prevalence of malnutrition in Chinese cancer patients. This study aims to evaluate the prevalence of malnutrition and quality of life (QOL) of Chinese patients with local regional, recurrent or metastatic cancer, to address the prognostic value of nutritional status and QOL on the survival of cancer patients in China and to validate the patient-generated subjective global assessment (PG-SGA) questionnaire in Chinese cancer patients.</p><p class="abstract"><strong>Methods:</strong> This is an observational, multi-centered, and hospital-based prospective cohort study. We aimed to recruit 50,000 cancer patients (age 18 and above) over an 8-year period. Data collection will occur within 48 hr after patients are admitted to hospital, 30-days after hospital admission, and the follow-up will be conducted 1-8 years after enrolment. The primary outcome is overall survival, and secondary outcomes are length of hospital stay and hospital costs. Factors measured are demographic characteristics, tumor characteristics, anthropometry measurements, hematological measurement, body composition, PG-SGA scores, Karnofsky performance status scores, and QLQ C30 scores. This protocol was approved by local ethical committees of all the participant hospitals.</p><p class="abstract"><strong>Conclusions: </strong>This multi-centered, large-scale, long-time follow-up prospective study will help diagnose malnutrition in cancer patients in China, and identify the related risk factors associated with the negative outcomes. The anticipated results will highlight the need for a truly scientific appraisal of nutrition therapy, and help to improve outcomes among cancer patients in China.</p><p class="abstract"><strong>Trial Registration: </strong>The trial has been registered with the Chinese Clinical Trial Registry, ChiCTR1800020329. Registered on 19 December 2018.<strong></strong></p>
Numerous studies indicate that non-coding RNAs (ncRNAs) have critical functions across biological processes, and single-nucleotide polymorphisms (SNPs) could contribute to diseases or traits through influencing ncRNA expression. However, the associations between SNPs and ncRNA expression are largely unknown. Therefore, genome-wide expression quantitative trait loci (eQTL) analysis to assess the effects of SNPs on ncRNA expression, especially in multiple cancer types, will help to understand how risk alleles contribute toward tumorigenesis and cancer development. Using genotype data and expression profiles of ncRNAs of >8700 samples from The Cancer Genome Atlas (TCGA), we developed a computational pipeline to systematically identify ncRNA-related eQTLs (ncRNA-eQTLs) across 33 cancer types. We identified a total of 6 133 278 and 721 122 eQTL-ncRNA pairs in cis-eQTL and trans-eQTL analyses, respectively. Further survival analyses identified 8312 eQTLs associated with patient survival times. Furthermore, we linked ncRNA-eQTLs to genome-wide association study (GWAS) data and found 262 332 ncRNA-eQTLs overlapping with known disease- and trait-associated loci. Finally, a user-friendly database, ncRNA-eQTL (http://ibi.hzau.edu.cn/ncRNA-eQTL), was developed for free searching, browsing and downloading of all ncRNA-eQTLs. We anticipate that such an integrative and comprehensive resource will improve our understanding of the mechanistic basis of human complex phenotypic variation, especially for ncRNA- and cancer-related studies.
The neuropathological hallmarks of Alzheimer’s disease (AD) include the presence of extracellular amyloid-β peptide (Aβ) in the form of amyloid plaques and neuronal loss. Neural stem cell (NSC) is being scrutinized as a promising cell replacement therapy for various neurodegenerative diseases. However, the unfavorable niche at the site of degenerative disease is hostile to the survival and differentiation of transplanted cells. Here, we undertook in vitro and in vivo works to examine whether a designer self-assemble peptide (DSP), which contains one functional domain Tyr-Ile-Gly-Ser-Arg (YIGSR) derived from laminin, promotes the survival and neuronal differentiation of NSC and behavioral improvement. We found that DSP could undergo spontaneous assembly into well-ordered nanofibers, and it not only facilitated the cell viability in normal culture condition, but also decreased the number of apoptotic cells induced by Aβ in vitro. NSC seeded in DSP showed much more neuronal differentiation than that seeded in self-assemble peptide (SP) or alone. In the AD model, NSC transplantation in DSP-treated AD rats demonstrated much more obvious cognitive rescue with restoration of learning/memory function compared with NSC transplantation in SP, NSC alone, or DSP alone treated ones. Interestingly, DSP enhanced the survival and neuronal differentiation of transplanted NSC. Apoptosis levels in the CA1 region and Aβ level in the hippocampus were significantly decreased in the group of NSC transplantation in DSP. Moreover, synaptic function, indicated by the expression of pre-synaptic protein synapsin-1, was restored and the secretion of anti-inflammatory and neurotrophic factors were increased, such as IL-10, brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and insulin-like growth factor 1 (IGF-1), while the expression of pro-inflammatory factors were decreased, such as TNF-α and IL-1β. These data firstly unveiled that the biomaterial DSP can maximize the therapeutic benefits of NSC transplantation for AD through improving the survival and differentiation of transplanted stem cells and promoting the effects of neuroprotection, anti-neuroinflammatory and paracrine action. Our results may have important clinical implications for the design of future NSC-based strategies using the biomaterials for various neurodegenerative diseases including AD.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-014-9069-y) contains supplementary material, which is available to authorized users.
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