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Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood-brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD.
The UNECE Sustainable Transport Division provides the secretariat services to WP.29, the World Forum that incorporates into its regulatory framework the technological innovations of vehicles to make them safer and more environmentally sound and thus contributing to the implementation of SDGs 3, 7, 9, 11 and 13.
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase (IDS) enzyme, resulting in cellular accumulation of glycosaminoglycans (GAGs) throughout the body. Treatment of MPS II remains a considerable challenge as current enzyme replacement therapies do not adequately control many aspects of the disease, including skeletal and neurological manifestations. We developed an IDS transport vehicle (ETV:IDS) that is engineered to bind to the transferrin receptor; this design facilitates receptor-mediated transcytosis of IDS across the blood-brain barrier and improves its distribution into the brain while maintaining distribution to peripheral tissues. Here we show that chronic systemic administration of ETV:IDS in a mouse model of MPS II reduced levels of peripheral and central nervous system GAGs, microgliosis, and neurofilament light chain, a biomarker of neuronal injury. Additionally, ETV:IDS rescued auricular and skeletal abnormalities when introduced in adult MPS II mice. These effects were accompanied by improvements in several neurobehavioral domains, including motor skills, sensorimotor gating, and learning and memory. Together, these results highlight the therapeutic potential of ETV:IDS for treating peripheral and central abnormalities in MPS II. DNL310, an investigational ETV:IDS molecule, is currently in clinical trials as a potential treatment for patients with MPS II.
IDPH licenses Emergency Medical Services provider agencies and their transport and non-transport vehicles to ensure compliance with equipment and staffing requirements, along with minimum build standards as adopted by the state and enforced through an inspection process. The Department also licenses stretcher vans, which must meet a defined set of safety feature requirements.
Riggs, whose county includes the popular ice-fishing destination Upper Red Lake, said conservation officers and county deputies have responded to several recent incidents of vehicles and wheelhouses falling through the ice. That includes three rescues on Upper Red Lake, Riggs said.
The Secretary of the Department of Transportation receives the authority to regulate the transportation of hazardous materials from the Hazardous Materials Transportation Act (HMTA), as amended and codified in 49 U.S.C. 5101 et seq. The Secretary is authorized to issue regulations to implement the requirements of 49 U.S.C. The Pipeline and Hazardous Materials Safety Administration (PHMSA) (formerly the Research and Special Provisions Administration (RSPA)) was delegated the responsibility to write the hazardous materials regulations, which are contained in 49 CFR Parts 100-180. In order to accomplish his responsibilities under the HMTA the Secretary "...may authorize any officer, employee, or agent to enter upon inspect, and examine, at reasonable times and in a reasonable manner, the records and properties of persons to the extent such records and properties relate to: (1) the manufacture, fabrication, marking, maintenance, reconditioning, repair, testing, or distribution of packages or containers for use by any "person" in the transportation of hazardous materials in commerce; or (2) the transportation or shipment by any "person" of hazardous materials in "commerce."
"No person may offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance with subpart G of Part 107 of this chapter, if applicable, and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized..."(49 CFR 171.2(a))
Most Federal Agencies including the Department of Defense are considered "offerors" when they ship hazardous materials by commercial carriers. In those rare instances where governmental agencies transport hazardous materials in commerce on government vehicles/aircraft, the agency is also considered a carrier. Contractors are fully subject to the requirements of the Federal hazardous materials transportation law.
The Uniformed Services of the United States generally are not subject to the commerce clause of the Constitution. Therefore, military shipments, transported on military vehicles or aircraft are not subject to Federal jurisdiction. However, many states require military movements by highway to conform to 49 CFR or compatible state regulations. DOD and Service Regulations also require compliance with 49 CFR Parts 100-180. When in peacetime, the military services procure commercial transportation, (offering into commerce), the military is engaged in commerce and required to comply with 49 CFR
"Persons" who offer for transportation, or transport in foreign, interstate or intrastate commerce: (a) any highway route controlled quantity of a Class 7 (radioactive) material; (b) more than 25 kg (55 lbs.) of a Division 1.1, 1.2, or 1.3 (explosive) material in a motor vehicle, rail car or freight container; (c) more than 1 L per package of a material extremely poisonous by inhalation; (d) a hazardous material in a bulk packaging having a capacity of 3,500 gals. for liquids or gases, or more than 468 cubic feet for solids; (e) a shipment in other than bulk packaging of 5,000 lbs. gross weight or more of one class of hazardous material for which the transport vehicle requires placarding; (f) any quantity of materials requiring placarding. The following are excepted from the registration requirement:
After January 1, 2005, the Federal Motor Carrier Safety Administration (FMCSA) requires motor carriers to obtain a Hazardous Materials Safety Permit (HMSP) prior to transporting certain highly hazardous materials. An HMSP is required to transport any of the following materials:
The Modal Agencies have established their own programs to prioritize their inspection activities of transporters of hazardous materials. Pipeline and Hazardous Materials Safety Administration, in addition to the Modal Agencies have selection criteria for shippers; "offerors", that are similar i.e. (1) Investigation of known shipper violations discovered during carrier audits, (2) Non-frivolous written complaints alleging violations of the Federal Hazardous Materials Regulations, (3) NRC and DOT 5800.1, spill and hazmat incident reports, (4) Referrals from other governmental agencies and special investigations targeting high risk hazardous materials such as explosives and certain radioactive materials. In almost all instances these shipper inspections are unannounced.
This list above contains some of the major responsibilities of HM carriers. Carrier and offeror (shipper) responsibilities frequently overlap. When a motor carrier performs a shipper function, the carrier is responsible for performing that function in accordance with 49 CFR. The cargo space of the vehicle should be suitable for the material being shipped. The vehicle itself must be in sound mechanical condition. The carrier must check to insure that the material offered by the shipper is properly described and packaged. In addition to the provisions of 49 CFR Parts 100-180, interstate motor carriers of placarded loads must comply with the hazardous materials requirements in 49 CFR Part 397.
Immediate notification of a hazardous materials incident by a carrier is required at the earliest practical moment for incidents that occur during the course of transportation (including loading, unloading, and temporary storage) in which as a direct result of the hazardous materials any one or more of the following occurs:
A written report shall be submitted on DOT Form F 5800.1 for all incidents involving the transportation of hazardous materials unless excepted. Detailed reporting requirements are contained in 171.16.
COMBUSTIBLE LIQUIDS Materials whose FP is greater than 141 F but less than 200EF are still regulated domestically as combustible liquids. Materials transported domestically only, whose FPs are 100 F up to 141 F may be reclassified as combustible in accordance with 173.120(b).
"ORM-D materials" are materials such as a consumer commodity, which although is subject to the regulations presents a limited hazard during transportation due to its form, quantity and packaging. Each ORM-D material and category of ORM-D material is listed in the 49 CFR 172.101 Table and 173.144.
Agricultural Operations
The transportation of agricultural products (see 49 CFR171.8) by highway may be excepted from some or all of the provisions of the Hazardous Materials Regulations when transported in accordance with the provisions of 49 CFR 173.5.