Paradoxes of Traffic Flow and Economics of Congestion Pricing

This paper utilizes a unique county-level dataset to examine technical efficiency and technology gap in China’s agriculture. We classify the counties into four regions with distinctive levels of economic development, and hence production technologies. A meta-frontier analysis is applied to the counties. We find that although the eastern counties have the highest efficiency scores with respect to the regional frontier but the northeastern region leads in terms of agricultural production technology nationwide. Meanwhile, the mean efficiency of the northeastern counties is particularly low, suggesting technology and knowledge diffusion within region might help to improve production efficiency and thus output.China’s grain production; County-level; Metafrontier; Stochastic production frontier; Technical efficiency

Original Article Neuroprotective effect of functionalized multi-walled carbon nanotubes on spinal cord injury in rats

Abstract: Traumatic injuries to the brain and spinal cord affect a large percentage of the world's population. However, there are currently no effective treatments for these central nervous system (CNS) injuries. In our study, we evaluated the neuroprotective role of functionalized multi-walled carbon nanotubes (MWCNTs) carrying brain derived neurotrophic factor (BNDF), nogo-66 receptor (NgR) and Ras homolog gene family member A (RhoA) in spinal cord injury (SCI). Our results showed that transfection into rat cortical neurons with BDNF-DNA significantly elevated the expression of BDNF both in vitro and in vivo. Meanwhile, transfection with NgR-siRNA and RhoA-siRNA resulted in an obvious down-regulation of NgR and RhoA in neuron cells and in injured spinal cords. In addition, the functionalized MWCNTs carrying BDNF-DNA, NgR-siRNA and RhoA-siRNA exhibited remarkable therapeutic effects on injured spinal cord. Taken together, our study demonstrates that functionalized MWCNTs have a potential therapeutic application on repair and regeneration of the CNS

Physical Association of PDK1 with AKT1 Is Sufficient for Pathway Activation Independent of Membrane Localization and Phosphatidylinositol 3 Kinase

Frequent activation of the AKT serine-threonine kinase in cancer confers resistance to therapy. AKT is activated by a multi-step process involving phosphatidylinositide (PtdIns) phosphate-mediated recruitment of AKT and its upstream kinases, including 3-Phosphoinositide-dependent kinase 1 (PDK1), to the inner surface of the cell membrane. PDK1 in the appropriate context phosphorylates AKT at threonine 308 (T308) to activate AKT. Whether PtdIns(3,4,5)Ps (PtdInsP3) binding and AKT membrane translocation mediate functions other than formation of a functional PDK1::AKT complex have not been fully elucidated. We fused complementary fragments of intensely fluorescent protein (IFP) to AKT1 and PDK1 to induce a stable complex to study the prerequisites of AKT1 phosphorylation and function. In the stabilized PDK1-IFPC::IFPN-AKT1 complex, AKT1 T308 phosphorylation was independent of PtdIns, as demonstrated by treatment with Phosphatidylinositol 3 Kinase (PI3K) inhibitors. Further when interaction with PtdIns and the cell membrane was prevented by creating PH-domain mutants of AKT1 (R25A) and PDK1 (R474A), AKT1 phosphorylation on T308 was maintained in the PDK1-IFPC::IFPN-AKT1 complex. The PDK1-IFPC::IFPN-AKT1 complex was sufficient for phosphorylation of known AKT substrates, and conferred resistance to inhibitors of PI3K (LY294002, PI103, GDC0941 and TGX286) but not inhibitors of the downstream TORC1 complex (rapamycin). Thus the locus of action of targeted therapeutics can be elucidated by the constitutively active AKT1 complex. Our data indicate that PtdIns and membrane localization are not required for AKT phosphorylation and activation, but rather serve to induce a functional physical interaction between PDK1 and AKT. The PDK1-IFPC::IFPN-AKT1 complex provides a cell-based platform to examine specificity of drugs targeting PI3K pathway components

Cost-effectiveness of sintilimab plus chemotherapy versus chemotherapy alone as first-line treatment of locally advanced or metastatic oesophageal squamous cell carcinoma

BackgroundSintilimab plus chemotherapy significantly prolongs overall survival (OS) for patients with advanced or metastatic oesophageal squamous cell carcinoma (OSCC). However, the cost-effectiveness of this high-priced therapy is currently unknown. We evaluated the cost-effectiveness of sintilimab plus chemotherapy vs chemotherapy alone as fist-line therapy in patients with advanced or metastatic OSCC from the perspective of Chinese healthcare system.MethodsA partitioned survival model consisting of 3 discrete health states was constructed to assess the cost and effectiveness of sintilimab plus chemotherapy vs chemotherapy as first-line treatment of OSCC. Key clinical data in the model came from the ORIENT-15 trial. Costs and utilities were collected from published sources. Life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefits (INHB), and incremental net monetary benefits (INMB) were calculated for the two treatment strategies. One-way and probabilistic sensitivity analyses were conducted to account for uncertainty and model stability. Additional subgroup and scenario analyses were performed.ResultsTreatment with sintilimab plus chemotherapy provided an additional 0.37 QALYs and an incremental cost of $8,046.58 compared with chemotherapy, which resulted in an ICER of$21,782.24 per QALY gained. One-way sensitivity analysis revealed that the model was most sensitive to utility of progression-free survival (PFS) and the cost of sintilimab. The probabilistic sensitivity analysis indicated that the probability of sintilimab plus chemotherapy being cost-effective was 0.01%, 76.80% and 98.60% at the threshold of 1, 2 or 3 times GDP per capita per QALY, respectively. Subgroup analysis found that all subgroups other than PD-L1 expression combined positive scores < 1 subgroup favored sintilimab plus chemotherapy treatment due to its association with positive INHBs by varying the hazard ratios for OS and PFS. The scenario analyses showed altering the time horizon of the model or fitting survival curves separately did not reverse results of the model.ConclusionSintilimab plus chemotherapy was associated with improved QALYs and an additional cost but was estimated to be cost-effective compared with chemotherapy alone as a first-line treatment for patients with advanced or metastatic OSCC at the commonly adopted willingness-to-pay threshold of 3 times GDP per capita per QALY in China

USP21 deubiquitylates Nanog to regulate protein stability and stem cell pluripotency

The homeobox transcription factor Nanog has a vital role in maintaining pluripotency and self-renewal of embryonic stem cells (ESCs). Stabilization of Nanog proteins is essential for ESCs. The ubiquitin–proteasome pathway mediated by E3 ubiquitin ligases and deubiquitylases is one of the key ways to regulate protein levels and functions. Although ubiquitylation of Nanog catalyzed by the ligase FBXW8 has been demonstrated, the deubiquitylase that maintains the protein levels of Nanog in ESCs yet to be defined. In this study, we identify the ubiquitin-specific peptidase 21 (USP21) as a deubiquitylase for Nanog, but not for Oct4 or Sox2. USP21 interacts with Nanog protein in ESCs in vivo and in vitro. The C-terminal USP domain of USP21 and the C-domain of Nanog are responsible for this interaction. USP21 deubiquitylates the K48-type linkage of the ubiquitin chain of Nanog, stabilizing Nanog. USP21-mediated Nanog stabilization is enhanced in mouse ESCs and this stabilization is required to maintain the pluripotential state of the ESCs. Depletion of USP21 in mouse ESCs leads to Nanog degradation and ESC differentiation. Overall, our results demonstrate that USP21 maintains the stemness of mouse ESCs through deubiquitylating and stabilizing Nanog

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin