Monoamine transporter ubiquitination and inward-open conformation synergistically maximize transporter endocytosis.

Monoamine transporters function in neuronal membranes to control extracellular concentrations of their substrates. Cell-surface expression of transporters is regulated by substrates and intracellular signaling, but the underlying mechanisms remain unclear. Here, we found that substrates of the dopamine transporter (DAT), amphetamine and dopamine, synergize with protein kinase C (PKC)-dependent DAT ubiquitination to markedly elevate clathrin-mediated endocytosis of DAT, which is accompanied by DAT movement out of plasma membrane protrusions with a negative curvature.

Low-affinity ligands of the epidermal growth factor receptor are long-range signal transmitters during collective cell migration of epithelial cells.

Epidermal growth factor receptor ligands (EGFRLs) consist of seven proteins. In stark contrast to the amassed knowledge concerning the epidermal growth factor receptors themselves, the extracellular dynamics of individual EGFRLs remain elusive. Here, employing fluorescent probes and a tool for triggering ectodomain shedding of EGFRLs, we show that EREG, a low-affinity EGFRL, exhibits the most rapid and efficient activation of EGFR in confluent epithelial cells and mouse epidermis.

Amphetamine Induces Sex-Dependent Loss of the Striatal Dopamine Transporter in Sensitized Mice.

Dopamine transporter (DAT) controls dopamine signaling in the brain through the reuptake of synaptically released dopamine. DAT is a target of abused psychostimulants such as amphetamine (Amph). Acute Amph administration induces transient DAT endocytosis, which, among other Amph effects on dopaminergic neurons, elevates extracellular dopamine.

Cbl and Cbl-b independently regulate EGFR through distinct receptor interaction modes.

Highly homologous E3 ubiquitin ligases, Cbl and Cbl-b, mediate ubiquitination of EGF receptor (EGFR), leading to its endocytosis and lysosomal degradation. Cbl and Cbl-b, are thought to function in a redundant manner by binding directly to phosphorylated Y1045 (pY1045) of EGFR and indirectly via the Grb2 adaptor. Unexpectedly, we found that inducible expression of Cbl or Cbl-b mutants lacking the E3 ligase activity but fully capable of EGFR binding does not significantly affect EGFR ubiquitination and endocytosis in human oral squamous cell carcinoma (HSC3) cells which endogenously express Cbl-b at a relatively high level.

Plating Versus Intramedullary Nailing of OTA/AO 43C1 and C2 Intra-articular Distal Tibia Fractures: A Propensity Score and Multivariate Analysis.

Objective: To compare rates of reduction loss, nonunion, and infection in intra-articular distal tibia fractures (IADTF) treated with limited open reduction internal fixation and intramedullary nailing (IMN) as compared to open reduction internal fixation with plate and screws (plate fixation [PF]).

Design: Retrospective review.

Setting: Level-I academic trauma center.

Work Productivity Loss After Minimally Displaced Complete Lateral Compression Pelvis Fractures.

Objective: To quantify work impairment and economic losses due to lost employment, lost work time (absenteeism), and lost productivity while working (presenteeism) after a lateral compression pelvic ring fracture. Secondarily, productivity loss of patients treated with surgical fixation versus nonoperative management was compared.

Design: Secondary analysis of a prospective, multicenter trial.

Evaluation of a novel anastomotic device in the animal model: A feasibility, safety, and efficacy study.

Background: A novel device was designed to assist with microvascular arterial anastomoses. This study compares the safety and efficacy of the anastomosis-assisting device with manual suturing in an ovine model.

Methods: Arteries with a diameter ranging from 2 to 4 mm were transected and anastomosed at four locations.

The Alkylamine Stimulant 1,3-Dimethylamylamine Exhibits Substrate-Like Regulation of Dopamine Transporter Function and Localization.

The alkylamine stimulant 1,3-dimethylamylamine (DMAA) is used nonmedically as an appetite suppressant and exercise performance enhancer despite adverse cardiovascular effects that have limited its legal status. There is scant research describing the mechanism of action of DMAA, making it difficult to gauge risks or therapeutic potential. An important molecular target of structurally related phenethylamines, such as amphetamine, for regulating mood, cognition, movement, and the development of substance use disorder is the dopamine transporter, which limits the range and magnitude of dopamine signaling via reuptake from the extracellular space.

Endocytic down-regulation of the striatal dopamine transporter by amphetamine in sensitized mice in sex-dependent manner.

Dopamine transporter (DAT) controls dopamine signaling in the brain through the reuptake of synaptically released dopamine. DAT is a target of abused psychostimulants such as amphetamine (Amph). Acute Amph is proposed to cause transient DAT endocytosis which among other Amph effects on dopaminergic neurons elevates extracellular dopamine.

Silicone breast implant rupture is more prevalent in the dominant limb side: A retrospective cohort study.

Background: Breast implant rupture is associated with multiple risk factors such as implant age, manufacturer, and a history of trauma to the breast. However, the exact mechanism of breast implant rupture remains unclear. We hypothesize that repetitive minor mechanical forces on the implant collectively play a significant role in the cascade that eventually leads to its rupture.

Outcomes Following Intramedullary Nailing of Select Periarticular Distal Tibia Fractures.

Intramedullary nailing (IMN) of periarticular distal tibia fractures may offer advantages compared to plating. This study aims to report on the outcomes of select periarticular distal tibia fractures treated with IMN. Patients over 17 years of age that underwent IMN for extraarticular distal tibia fractures (Osteosynthesefragen/Orthopaedic Trauma Association [AO/OTA] 43-A), partial articular with associated segmental shaft component (43-B), and simple intraarticular (43-C1/2) at a Level I trauma center were included.

BladeShield 101: A Novel Prehospital Digital Wearable Combat Casualty Card.

Background: The Israeli Defense Forces-Medical Corps (IDF-MC) focuses on reducing preventable death by improving prehospital trauma care. High quality documentation of care can serve casualty care and to improve future care. Currently, paper casualty cards are used for documentation.

Trends in prehospital pain management: two decades of point-of-injury care.

Background: Pain control in trauma is an integral part of treatment in combat casualty care. More soldiers injured on the battlefield need analgesics for pain than life-saving interventions (LSIs). Early treatment of pain improves outcomes after injury, while inadequate treatment leads to higher rates of post-traumatic stress disorder (PTSD).

Patterns in vehicle-ramming attacks.

Background: Vehicle-ramming attacks have become a common tactic for terror organizations worldwide. However, the medical implications of vehicle-ramming attacks remain unknown.

Objectives: To investigate the characteristics of vehicle-ramming attack incidents and casualties in order to assist in guiding the policy of medical organizations.

Emergent exploratory thoracotomy with military casualties: contemporary prehospital management and outcome (see editorial page 619).

Background: Chest trauma is among the most common types of trauma, corresponding to 10% of trauma patients admitted to hospitals. In the military setting, thoracic trauma was reported as a significant cause of death. With well-timed treatment, chest trauma is regarded as survivable.

The association between helicopter emergency medical services and early casualty survival: a nationwide study.

Background: Helicopter emergency medical services (HEMS) allow for shorter transport duration in long-distance evacuations and facilitate advanced en-route medical care access. Studies comparing HEMS with ground emergency medical services (GEMS), including the outcome of prehospital mortality, are lacking.

Objective: This study aimed to evaluate the association between HEMS and early mortality in Israel.

CRISPR/Cas9 Gene Editing of HeLa Cells to Tag Proteins with mNeonGreen.

Subcellular localization dynamics of proteins involved in signal transduction processes is crucial in determining the signaling outcome. However, there is very limited information about the localization of endogenous signaling proteins in living cells. For example, biochemical mechanisms underlying the signaling pathway from epidermal growth factor (EGF) receptor (EGFR) to RAS-RAF and ERK1/2/MAPK are well understood, whereas the operational domains of this pathway in the cell remain poorly characterized.

Time-resolved proximity labeling of protein networks associated with ligand-activated EGFR.

Ligand binding to the EGF receptor (EGFR) triggers multiple signal-transduction processes and promotes endocytosis of the receptor. The mechanisms of EGFR endocytosis and its cross-talk with signaling are poorly understood. Here, we combine peroxidase-catalyzed proximity labeling, isobaric peptide tagging, and quantitative mass spectrometry to define the dynamics of the proximity proteome of ligand-activated EGFR.

Ten-year reduction in thoracic injury-related mortality among Israel Defense Forces soldiers.

Introduction: This study aims to describe injury patterns, prehospital interventions and mortality rates of combat-related thoracic injuries during the past decade among Israel Defense Forces (IDF) soldiers before and after implementation of the 2012 IDF-Military Corps plan which included the publication of clinical practice guidelines (CPGs) for thoracic injuries, emphasis on adequate torso protection, introduction of modern life-saving procedures and encouragement of rapid evacuation.

Methods: The IDF prehospital trauma registry was reviewed to identify all patients who sustained thoracic injuries from January 2006 to December 2017. IDF soldiers who were injured, died of wounds or killed in action (KIA) were included.

EGFR-RAS-MAPK signaling is confined to the plasma membrane and associated endorecycling protrusions.

The subcellular localization of RAS GTPases defines the operational compartment of the EGFR-ERK1/2 signaling pathway within cells. Hence, we used live-cell imaging to demonstrate that endogenous KRAS and NRAS tagged with mNeonGreen are predominantly localized to the plasma membrane. NRAS was also present in the Golgi apparatus and a tubular, plasma-membrane derived endorecycling compartment, enriched in recycling endosome markers (TERC).