PI3K and PTEN are the second and third most highly mutated proteins in cancer following only p53. Their actions oppose each other. PI3K phosphorylates signaling lipid PIP2 to PIP3 PTEN dephosphorylates it back. Driver mutations in both proteins accrue PIP3 PIP3 recruits AKT and PDK1 to the membrane, promoting cell-cycle progression. Here we review phosphorylation events and mutations in autoinhibition in PI3K and PTEN from the structural standpoint. Our purpose is to clarify how they control the autoinhibited states. In autoinhibition, a segment or a subunit of the protein occludes its functional site. Protein-protein interfaces are often only marginally stable, making them sensitive to changes in conditions in living cells. Phosphorylation can stabilize or destabilize the interfaces. Driver mutations commonly destabilize them. In analogy to "passenger mutations," we coin "passenger phosphorylation" to emphasize that the presence of a phosphorylation recognition sequence logo does not necessarily imply function.  https://www.selleckchem.com/products/pu-h71.html  Rather, it may simply reflect a statistical occurrence. In both PI3K and PTEN, autoinhibiting phosphorylation events are observed in the occluding "piece." In PI3Kα, the "piece" is the p85α subunit. In PTEN, it is the C-terminal segment. In both enzymes the stabilized interface covers the domain that attaches to the membrane. Driver mutations that trigger rotation of the occluding piece or its deletion prompt activation. To date, both enzymes lack specific, potent drugs. We discuss the implications of detailed structural and mechanistic insight into oncogenic activation and how it can advance allosteric precision oncology.
  To determine the prevalence of invasive bacterial infections (IBIs) and adverse events in afebrile infants with acute otitis media (AOM).
 
  We conducted a 33-site cross-sectional study of afebrile infants ≤90 days of age with AOM seen in emergency departments from 2007 to 2017. Eligible infants were identified using emergency department diagnosis codes and confirmed by chart review. IBIs (bacteremia and meningitis) were determined by the growth of pathogenic bacteria in blood or cerebrospinal fluid (CSF) culture. Adverse events were defined as substantial complications resulting from or potentially associated with AOM. We used generalized linear mixed-effects models to identify factors associated with IBI diagnostic testing, controlling for site-level clustering effect.
 
  Of 5270 infants screened, 1637 met study criteria. None of the 278 (0%; 95% confidence interval [CI] 0%-1.4%) infants with blood cultures had bacteremia; 0 of 102 (0%; 95% CI 0%-3.6%) with CSF cultures had bacterial meningitis; 2 of 645 (0.3%; 95% CI 0.1%-1.1%) infants with 30-day follow-up had adverse events, including lymphadenitis (1) and culture-negative sepsis (1). Diagnostic testing for IBI varied across sites and by age; overall, 278 (17.0%) had blood cultures, and 102 (6.2%) had CSF cultures obtained. Compared with infants 0 to 28 days old, older infants were less likely to have blood cultures (
  < .001) or CSF cultures (
  < .001) obtained.
 
  Afebrile infants with clinician-diagnosed AOM have a low prevalence of IBIs and adverse events; therefore, outpatient management without diagnostic testing may be reasonable.
 Afebrile infants with clinician-diagnosed AOM have a low prevalence of IBIs and adverse events; therefore, outpatient management without diagnostic testing may be reasonable.
  During the current drug overdose crisis, the United States is experiencing a significant number of overdose deaths, hospitalizations, and emergency department visits. Given the vulnerability of young persons to substance use, it is important to assess how this crisis affects the nation's youth. In this study, we investigate trends in suspected nonfatal drug-related overdoses (all-drugs, opioids, heroin, and stimulants) among youth using syndromic surveillance data from 2016 to 2019.
 
  A retrospective analysis of emergency department syndromic surveillance data were used to detect quarterly trends in suspected drug overdoses from April 2016 through September 2019 among youth aged 0 to 10, 11 to 14, and 15 to 24 years. Syndrome definitions were developed using chief complaint free-text and discharge diagnosis codes to identify overdoses involving all-drugs, opioids, heroin, and stimulants. Pearson χ
  tests detected quarter-to-quarter changes, and joinpoint regression analysis assessed trends over time.
 
  On average, there was a 2.0% increase for youth aged 0 to 10 years and a 2.3% increase for youth aged 11 to 14 years for suspected all-drug overdoses. Suspected heroin overdoses decreased by an average of 3.3% per quarter for youth aged 15 to 24 years. Among all age groups, suspected stimulant overdoses increased across the study period, 3.3% for 0 to 10-year-olds, 4.0% for 11- to 14-year-olds, and 2.3% for 15- to 24-year-olds.
 
  Suspected stimulant-involved drug overdoses appear to be rising among youth. These findings could inform targeted interventions, such as stimulant-focused prevention, and comprehensive approaches, including school-based prevention and other strategies to lower morbidity and mortality.
 Suspected stimulant-involved drug overdoses appear to be rising among youth. These findings could inform targeted interventions, such as stimulant-focused prevention, and comprehensive approaches, including school-based prevention and other strategies to lower morbidity and mortality.Hepatocytes metabolize energy-rich cytoplasmic lipid droplets (LDs) in the lysosome-directed process of autophagy. An organelle-selective form of this process (macrolipophagy) results in the engulfment of LDs within double-membrane delimited structures (autophagosomes) before lysosomal fusion. Whether this is an exclusive autophagic mechanism used by hepatocytes to catabolize LDs is unclear. It is also unknown whether lysosomes alone might be sufficient to mediate LD turnover in the absence of an autophagosomal intermediate. We performed live-cell microscopy of hepatocytes to monitor the dynamic interactions between lysosomes and LDs in real-time. We additionally used a fluorescent variant of the LD-specific protein (PLIN2) that exhibits altered fluorescence in response to LD interactions with the lysosome. We find that mammalian lysosomes and LDs undergo interactions during which proteins and lipids can be transferred from LDs directly into lysosomes. Electron microscopy (EM) of primary hepatocytes or hepatocyte-derived cell lines supports the existence of these interactions.