Disruption of splicing-regulatory elements using CRISPR/Cas9 to rescue spinal muscular atrophy in human iPSCs and mice

We here report a genome-editing strategy to correct spinal muscular atrophy (SMA). Rather than directly targeting the pathogenic exonic mutations, our strategy employed Cas9 and guide-sgRNA for the targeted disruption of intronic splicing-regulatory elements. We disrupted intronic splicing silencers (ISSs, including ISS-N1 and ISS + 100) of survival motor neuron (SMN) 2, a key modifier gene of SMA, to enhance exon 7 inclusion and full-length SMN expression in SMA iPSCs. Survival of splicing-corrected iPSC-derived motor neurons was rescued with SMN restoration. Furthermore, co-injection of Cas9 mRNA from Streptococcus pyogenes (SpCas9) or Cas9 from Staphylococcus aureus (SaCas9) alongside their corresponding sgRNAs targeting ISS-N1 into zygotes rescued 56% and 100% of severe SMA transgenic mice (Smn , SMN2 ). The median survival of the resulting mice was extended to >400 days. Collectively, our study provides proof-of-principle for a new strategy to therapeutically intervene in SMA and other RNA-splicing-related diseases. -/- tg/

Tirofiban for Stroke without Large or Medium-Sized Vessel Occlusion

The effects of the glycoprotein IIb/IIIa receptor inhibitor tirofiban in patients with acute ischemic stroke but who have no evidence of complete occlusion of large or medium-sized vessels have not been extensively studied. In a multicenter trial in China, we enrolled patients with ischemic stroke without occlusion of large or medium-sized vessels and with a National Institutes of Health Stroke Scale score of 5 or more and at least one moderately to severely weak limb. Eligible patients had any of four clinical presentations: ineligible for thrombolysis or thrombectomy and within 24 hours after the patient was last known to be well; progression of stroke symptoms 24 to 96 hours after onset; early neurologic deterioration after thrombolysis; or thrombolysis with no improvement at 4 to 24 hours. Patients were assigned to receive intravenous tirofiban (plus oral placebo) or oral aspirin (100 mg per day, plus intravenous placebo) for 2 days; all patients then received oral aspirin until day 90. The primary efficacy end point was an excellent outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. Secondary end points included functional independence at 90 days and a quality-of-life score. The primary safety end points were death and symptomatic intracranial hemorrhage. A total of 606 patients were assigned to the tirofiban group and 571 to the aspirin group. Most patients had small infarctions that were presumed to be atherosclerotic. The percentage of patients with a score of 0 or 1 on the modified Rankin scale at 90 days was 29.1% with tirofiban and 22.2% with aspirin (adjusted risk ratio, 1.26; 95% confidence interval, 1.04 to 1.53, P = 0.02). Results for secondary end points were generally not consistent with the results of the primary analysis. Mortality was similar in the two groups. The incidence of symptomatic intracranial hemorrhage was 1.0% in the tirofiban group and 0% in the aspirin group. In this trial involving heterogeneous groups of patients with stroke of recent onset or progression of stroke symptoms and nonoccluded large and medium-sized cerebral vessels, intravenous tirofiban was associated with a greater likelihood of an excellent outcome than low-dose aspirin. Incidences of intracranial hemorrhages were low but slightly higher with tirofiban

Methylprednisolone as Adjunct to Endovascular Thrombectomy for Large-Vessel Occlusion Stroke

Importance It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy. Objective To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO. Design, Setting, and Participants This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023.InterventionsEligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy. Main Outcomes and Measures The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours. Results Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo. Conclusions and Relevance Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability.Trial RegistrationChiCTR.org.cn Identifier: ChiCTR210005172

A study on impacts and feasibility of kra canal construction on Singapore and other stakeholders

Kra Canal is a proposed canal to be built in Isthmus of Kra, Thailand. The Kra Canal project plans to cut a canal through Southern Thailand, connecting the Gulf of Thailand to the Andaman Sea. The canal offers an alternative route to Malacca Straits, which is expected to affect Thailand vastly, revolutionize the shipping industry and also impact on the neighbouring countries. The study is conducted using primary and secondary research. Secondary research involved analysing of data and information from existing studies. Primary research such as online surveys and interviews which serve as supplements to the secondary research, substantiating findings from existing studies and provide a common understanding of the project. This paper focused on the impacts of Kra Canal on Thailand and assessed the feasibility of the project. It is mutually believed that Kra Canal project may generate a positive economic impact to Thailand on a whole, however, at the same time welding social problems in addition to its current plight. That been said, Thai government needs to evaluate the pros and cons of the project from a bigger picture, before deciding on its involvements. Moving on, feasibility studies revealed a pessimistic future of the project. The study identified the push and pull factors behind this project, and evaluated them in correspondence with the primary research findings. The benefits of the project seem vague; the cost savings may not be excessive, there may even be additional cost incurred as port due. On the other hand, the underlying problems are salient, as the project appears to place Thailand’s social stability and sovereignty at stake. Hence, to the potential investors and driving forces behind the project, it seems rather unworthy to venture forward; within the scope of the research.Bachelor of Science (Maritime Studies

Joint Power Control and Scheduling for Context-Aware Unicast Cellular Networks

International audienceWith the widely use of smart devices and rapid development of communication technologies, it becomes easier for base stations to obtain the context information of users. The context information can be utilized to optimize system resource allocation. This paper focuses on context-aware unicast cellular networks. Assuming that some channel state information (CSI) can be predicted based on user context such as user location and moving pattern, joint power control and transmission scheduling is applied to minimize the transmission energy consumption. By reducing the energy minimization problem to a semi-assignment problem, our proposed algorithm can find the optimal solution in polynomial time. Simulation results show that the proposed context-aware scheme outperforms the traditional round-robin scheduler and opportunistic scheduler, which do not consider the feature of context-awareness

Context-aware wireless broadcast for next generation cellular networks

International audienceThis paper considers the energy minimization problem for wireless broadcast networks. One important feature is that user context is taken into consideration, integrated with network coding technique. Assuming that the user context, i.e., channel state information (CSI) can be predicted or estimated by using user location and moving pattern, power allocation is optimized to minimize energy consumption. It is proved NP-hard to find the optimal solution. By formulating the minimization problem into a binary integer programming (BLP) problem, the optimal solution can be obtained. Considering the high complexity of BLP, a heuristic algorithm is also proposed. Simulation results show that the proposed context-aware algorithms can reduce energy consumption up to 98%, compared with the scheme without using context information

Monetary Valuation of PM10-Related Health Risks in Beijing China: The Necessity for PM10 Pollution Indemnity

Severe health risks caused by PM10 (particulate matter with an aerodynamic diameter ≤10 μm) pollution have induced inevitable economic losses and have rendered pressure on the sustainable development of society as a whole. In China, with the “Polluters Pay Principle”, polluters should pay for the pollution they have caused, but how much they should pay remains an intractable problem for policy makers. This paper integrated an epidemiological exposure-response model with economics methods, including the Amended Human Capital (AHC) approach and the Cost of Illness (COI) method, to value the economic loss of PM10-related health risks in 16 districts and also 4 functional zones in Beijing from 2008 to 2012. The results show that from 2008 to 2012 the estimated annual deaths caused by PM10 in Beijing are around 56,000, 58,000, 63,000, 61,000 and 59,000, respectively, while the economic losses related to health damage increased from around 23 to 31 billion dollars that PM10 polluters should pay for pollution victims between 2008 and 2012. It is illustrated that not only PM10 concentration but also many other social economic factors influence PM10-related health economic losses, which makes health economic losses show a time lag discrepancy compared with the decline of PM10 concentration. In conclusion, health economic loss evaluation is imperative in the pollution indemnity system establishment and should be considered for the urban planning and policy making to control the burgeoning PM10 health economic loss

TopoLAP: Topology Recovery for Building Reconstruction by Deducing the Relationships between Linear and Planar Primitives

Limited by the noise, missing data and varying sampling density of the point clouds, planar primitives are prone to be lost during plane segmentation, leading to topology errors when reconstructing complex building models. In this paper, a pipeline to recover the broken topology of planar primitives (TopoLAP) is proposed to reconstruct level of details 3 (LoD3) models. Firstly, planar primitives are segmented from the incomplete point clouds and feature lines are detected both from point clouds and images. Secondly, the structural contours of each plane segment are reconstructed by subset selection from intersections of these feature lines. Subsequently, missing planes are recovered by plane deduction according to the relationships between linear and planar primitives. Finally, the manifold and watertight polyhedral building models are reconstructed based on the optimized PolyFit framework. Experimental results demonstrate that the proposed pipeline can handle partial incomplete point clouds and reconstruct the LoD3 models of complex buildings automatically. A comparative analysis indicates that the proposed method performs better to preserve sharp edges and achieves a higher fitness and correction rate than rooftop-based modeling and the original PolyFit algorithm