The SLC36 transporter Pathetic is required for neural stem cell proliferation and for brain growth under nutrition restriction

Abstract: Background: Drosophila neuroblasts (NBs) are neural stem cells whose maintenance relies on Notch activity. NBs proliferate throughout larval stages to generate a large number of adult neurons. Their proliferation is protected under conditions of nutrition restriction but the mechanisms responsible are not fully understood. As amino acid transporters (Solute Carrier transporters, SLCs), such as SLC36, have important roles in coupling nutrition inputs to growth pathways, they may have a role in this process. For example, an SLC36 family transporter Pathetic (Path) that supports body size and neural dendrite growth in Drosophila, was identified as a putative Notch target in genome-wide studies. However, its role in sustaining stem cell proliferation and maintenance has not been investigated. This study aimed to investigate the function of Path in the larval NBs and to determine whether it is involved in protecting them from nutrient deprivation. Methods: The expression and regulation of Path in the Drosophila larval brain was analysed using a GFP knock-in allele and reporter genes containing putative Notch regulated enhancers. Path function in NB proliferation and overall brain growth was investigated under different nutrition conditions by depleting it from specific cell types in the CNS, using mitotic recombination to generate mutant clones or by directed RNA-interference. Results: Path is expressed in both NBs and glial cells in the Drosophila CNS. In NBs, path is directly targeted by Notch signalling via Su(H) binding at an intronic enhancer, PathNRE. This enhancer is responsive to Notch regulation both in cell lines and in vivo. Loss of path in neural stem cells delayed proliferation, consistent with it having a role in NB maintenance. Expression from pathNRE was compromised in conditions of amino acid deprivation although other Notch regulated enhancers are unaffected. However, NB-expressed Path was not required for brain sparing under amino acid deprivation. Instead, it appears that Path is important in glial cells to help protect brain growth under conditions of nutrient restriction. Conclusions: We identify a novel Notch target gene path that is required in NBs for neural stem cell proliferation, while in glia it protects brain growth under nutrition restriction

Developing composite indicators for ecological water quality assessment based on network interactions and expert judgment

Increasingly, composite indicators and multi-criteria approaches are applied in environmental assessment and decision-making, including the EU Water Framework Directive. For example, integrated evaluation of aquatic ecosystem conditions and functioning usually involves a group of criteria, such as biological organisms and communities, physicochemical and hydromorphological variables, which are measured individually and combined by a weighted linear function into an overall 'score’. We argue that the network interactions of evaluation components are useful information for expert judgments, which have not been sufficiently considered in existing multi-criteria combination strategies in environmental assessment and management. Built upon the Analytic Network Process and demonstrated with the Chishui River Basin in China, this paper introduces a network-based expert judgment approach to construct ecological water quality indicators, and to determine and adjust their variable weight settings with information of interaction networks. This approach has potential to construct composite indicators for a broad environmental context.</p

Early-onset Alzheimer’s disease with depression as the first symptom: a case report with literature review

BackgroundAlzheimer’s disease is a common neurodegenerative disease, and patients with early-onset Alzheimer’s disease (onset age &lt; 65 years) often have atypical symptoms, which are easily misdiagnosed and missed. Multimodality neuroimaging has become an important diagnostic and follow-up method for AD with its non-invasive and quantitative advantages.Case presentationWe report a case of a 59-year-old female with a diagnosis of depression at the age of 50 after a 46-year-old onset and a 9-year follow-up observation, who developed cognitive dysfunction manifested by memory loss and disorientation at the age of 53, and eventually developed dementia. Combined with neuropsychological scales (MMSE and MOCA scores decreased year by year and finally reached the dementia criteria) and the application of multimodal imaging. MRI showed that the hippocampus atrophied year by year and the cerebral cortex was extensively atrophied. 18F-FDG PET image showed hypometabolism in right parietal lobes, bilateral frontal lobes, bilateral joint parieto-temporal areas, and bilateral posterior cingulate glucose metabolism. The 18F-AV45 PET image showed the diagnosis of early-onset Alzheimer’s disease was confirmed by the presence of Aβ deposits in the cerebral cortex.ConclusionEarly-onset Alzheimer’s disease, which starts with depression, often has atypical symptoms and is prone to misdiagnosis. The combination of neuropsychological scales and neuroimaging examinations are good screening tools that can better assist in the early diagnosis of Alzheimer’s disease.Graphical Abstrac

WenTong HuoXue Cream Can Inhibit the Reduction of the Pain-Related Molecule PLC- β

WenTong HuoXue Cream (WTHX-Cream) has been shown to effectively alleviate clinical symptoms of diabetic peripheral neuropathy (DPN). This study investigated the gene and protein expression of the pain-related molecule PLC-β3 in the dorsal root ganglion (DRG) of DPN rats. 88 specific pathogen-free male Wistar rats were randomly divided into placebo (10 rats) and DPN model (78 rats) groups, and the 78 model rats were used to establish the DPN model by intraperitoneal injection of streptozotocin and were then fed a high-fat diet for 8 weeks. These rats were randomly divided into the model group, the high-, medium-, and low-dose WTHX-Cream + metformin groups, the metformin group, the capsaicin cream group, and the capsaicin cream + metformin group. After 4 weeks of continuous drug administration, the blood glucose, body weight, behavioral indexes, and sciatic nerve conduction velocity were measured. The pathological structure of the DRG and the sciatic nerve were observed. PLC-β3 mRNA and protein levels in the DRG of rats were measured. Compared with the model group, the high-dose WTHX-Cream group showed increased sciatic nerve conduction velocity, improved sciatic nerve morphological changes, and increased expression of PLC-β3 mRNA and protein in the DRG. This study showed that WTHX-Cream improves hyperalgesia symptoms of DPN by inhibiting the reduction of PLC-β3 mRNA and protein expression in the diabetic DRG of DPN rats

Effects of phonon interference through long range interatomic bonds on thermal interface conductance

We investigate the role of two-path destructive phonon interference induced by interatomic bonds beyond the nearest neighbor in the thermal conductance of a silicon-germanium-like metasurface. Controlled by the ratio between the second and first nearest-neighbor harmonic force constants, the thermal conductance across a germanium atomic plane in the silicon lattice exhibits a trend switch induced by the destructive interference of the nearest-neighbor phonon path with a direct path bypassing the defect atoms. We show that bypassing of the heavy isotope impurity is crucial to the realization of the local minimum in the thermal conductance. We highlight the effect of the second phonon path on the distinct behaviors of the dependence of the thermal conductance on the impurity mass ratio. All our conclusions are confirmed both by Green’s Function calculations for the equivalent quasi-1D lattice models and by molecular dynamics simulations

Causal effect of PM1 on morbidity of cause-specific respiratory diseases based on a negative control exposure

Background: Extensive studies have linked PM2.5 and PM10 with respiratory diseases (RD). However, few is known about causal association between PM1 and morbidity of RD. We aimed to assess the causal effects of PM1 on cause-specific RD. Methods: Hospital admission data were obtained for RD during 2014 and 2019 in Beijing, China. Negative control exposure and extreme gradient boosting with SHapley Additive exPlanation was used to explore the causality and contribution between PM1 and RD. Stratified analysis by gender, age, and season was conducted. Results: A total of 1,183,591 admissions for RD were recorded. Per interquartile range (28 μg/m3) uptick in concentration of PM1 corresponded to a 3.08% [95% confidence interval (CI): 1.66%–4.52%] increment in morbidity of total RD. And that was 4.47% (95% CI: 2.46%–6.52%) and 0.15% (95% CI: 1.44%-1.78%), for COPD and asthma, respectively. Significantly positive causal associations were observed for PM1 with total RD and COPD. Females and the elderly had higher effects on total RD, COPD, and asthma only in the warm months (Z = 3.03, P = 0.002; Z = 4.01, P \u3c 0.001; Z = 3.92, P \u3c 0.001; Z = 2.11, P = 0.035; Z = 2.44, P = 0.015). Contribution of PM1 ranked first, second and second for total RD, COPD, and asthma among air pollutants. Conclusion: PM1 was causally associated with increased morbidity of total RD and COPD, but not causally associated with asthma. Females and the elderly were more vulnerable to PM1-associated effects on RD

MRI radiomics-based interpretable model and nomogram for preoperative prediction of Ki-67 expression status in primary central nervous system lymphoma

ObjectivesTo investigate the value of interpretable machine learning model and nomogram based on clinical factors, MRI imaging features, and radiomic features to predict Ki-67 expression in primary central nervous system lymphomas (PCNSL).Materials and methodsMRI images and clinical information of 92 PCNSL patients were retrospectively collected, which were divided into 53 cases in the training set and 39 cases in the external validation set according to different medical centers. A 3D brain tumor segmentation model was trained based on nnU-NetV2, and two prediction models, interpretable Random Forest (RF) incorporating the SHapley Additive exPlanations (SHAP) method and nomogram based on multivariate logistic regression, were proposed for the task of Ki-67 expression status prediction.ResultsThe mean dice Similarity Coefficient (DSC) score of the 3D segmentation model on the validation set was 0.85. On the Ki-67 expression prediction task, the AUC of the interpretable RF model on the validation set was 0.84 (95% CI:0.81, 0.86; p &lt; 0.001), which was a 3% improvement compared to the AUC of the nomogram. The Delong test showed that the z statistic for the difference between the two models was 1.901, corresponding to a p value of 0.057. In addition, SHAP analysis showed that the Rad-Score made a significant contribution to the model decision.ConclusionIn this study, we developed a 3D brain tumor segmentation model and used an interpretable machine learning model and nomogram for preoperative prediction of Ki-67 expression status in PCNSL patients, which improved the prediction of this medical task.Clinical relevance statementKi-67 represents the degree of active cell proliferation and is an important prognostic parameter associated with clinical outcomes. Non-invasive and accurate prediction of Ki-67 expression level preoperatively plays an important role in targeting treatment selection and patient stratification management for PCNSL thereby improving prognosis

Investigating novel direct Notch targets in Drosophila neural stem cells

Notch signalling is an evolutionary highly conserved signalling pathway. It plays various important roles in the regulation of many fundamental cellular processes such as proliferation, stem cell maintenance and differentiation during embryonic and adult development. Notch signalling has a simple transduction pathway. Upon Notch ligand binding to the receptor, the Notch intracellular domain (NICD) is released into the nucleus. The nuclear NICD interacts with the DNA-binding protein Suppressor of Hairless (Su(H)) to activate the expression of target genes, which are silenced by the Su(H)-corepressor complex in the absence of Notch activity. The functions of Notch are very context-dependent, making it important to identify the Notch regulated genes in different processes. Neural stem cells (NSCs) are cells that can divide and differentiate into all kinds of cells within the brain while they self-renew. Notch signalling is one of the key regulators in maintaining NSCs and performs a similar function in both Drosophila and vertebrate NSCs. Drosophila NSCs serve as an ideal model for studying the relationship between Notch function and stem cell behaviours. Although many target genes, such as the Hes genes, have been identified, they cannot fully account for the diversity of Notch responses. Therefore, further functional study of more potential target genes is needed to gain understanding about Notch-regulated NSC maintenance. In this thesis, a group of potential direct Notch target genes are examined for their responsiveness to Notch regulation and their functions in Drosophila NSCs. Previous genome-wide study in the Bray lab has found a number of potential Notch target genes in the Drosophila larval brain, with the characteristics of Notch transcription factor Su(H) binding and mRNA upregulation by Notch over-activation (Zacharioudaki et al. 2016). I first examined the Notch responsive element (NRE) activity of these potential Notch targets and their regulation by Notch both in vivo and in cell lines. The presented findings validated path, cables and Asph as direct Notch target genes in Drosophila NSCs, while syp, lola and Fer2 do not exhibit characteristics of Notch responsive targets in NSCs. The functional roles of two of the responsive genes, path and cables, were subsequently explored in Drosophila larval brains. Firstly, I found that Path, a potential amino acid transporter, is not only important for protecting NSC proliferation under normal and abnormal conditions through integrating growth pathways, but is also required for protecting brain growth under nutrition deprivation. Secondly, the cables gene was connected to a distal NRE through knocking out the suspected NRE region and the gene itself using the CRISPR/Cas9 technique. Subsequent experiments revealed that cables is also required for NSC proliferation. In summary, a group of direct Notch target genes were validated and as a consequence two genes that are important for protecting NSC proliferation were identified.China Scholarship Council, Cambridge Oversea Trust

The SLC36 transporter Pathetic is required for neural stem cell proliferation and for brain growth under nutrition restriction

Abstract: Background: Drosophila neuroblasts (NBs) are neural stem cells whose maintenance relies on Notch activity. NBs proliferate throughout larval stages to generate a large number of adult neurons. Their proliferation is protected under conditions of nutrition restriction but the mechanisms responsible are not fully understood. As amino acid transporters (Solute Carrier transporters, SLCs), such as SLC36, have important roles in coupling nutrition inputs to growth pathways, they may have a role in this process. For example, an SLC36 family transporter Pathetic (Path) that supports body size and neural dendrite growth in Drosophila, was identified as a putative Notch target in genome-wide studies. However, its role in sustaining stem cell proliferation and maintenance has not been investigated. This study aimed to investigate the function of Path in the larval NBs and to determine whether it is involved in protecting them from nutrient deprivation. Methods: The expression and regulation of Path in the Drosophila larval brain was analysed using a GFP knock-in allele and reporter genes containing putative Notch regulated enhancers. Path function in NB proliferation and overall brain growth was investigated under different nutrition conditions by depleting it from specific cell types in the CNS, using mitotic recombination to generate mutant clones or by directed RNA-interference. Results: Path is expressed in both NBs and glial cells in the Drosophila CNS. In NBs, path is directly targeted by Notch signalling via Su(H) binding at an intronic enhancer, PathNRE. This enhancer is responsive to Notch regulation both in cell lines and in vivo. Loss of path in neural stem cells delayed proliferation, consistent with it having a role in NB maintenance. Expression from pathNRE was compromised in conditions of amino acid deprivation although other Notch regulated enhancers are unaffected. However, NB-expressed Path was not required for brain sparing under amino acid deprivation. Instead, it appears that Path is important in glial cells to help protect brain growth under conditions of nutrient restriction. Conclusions: We identify a novel Notch target gene path that is required in NBs for neural stem cell proliferation, while in glia it protects brain growth under nutrition restriction