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The history of the learning design and technology field for the length of the twentieth century is well documented, however, events after the year 2000, even our lived histories, are missing from important timelines and discussions. This article is an attempt to describe the history of events in the educational technology and research field from the start of the twenty-first century to the global COVD-19 Pandemic. This historical overview reflects on these events and their significance to the field’s identity and future.

Infants show an interesting asymmetry in face processing: They are more fluent in processing female faces than they are at processing male faces. We hypothesize that such processing asymmetry results from greater experience with female faces than with male faces early in development. Asymmetrical face processing may have longlasting implications for development of face recognition, development of knowledge structures regarding females and males, and social-information processing. We encourage researchers to use both female and male faces in their face-perception research and to conduct separate analyses for female and male faces.

The Federal Bureau of Prisons limits hepatitis C therapy to those inmates with certain biochemical abnormalities. To evaluate this protocol, an analysis was done on data collected on hepatitis C infected inmates in the Louisiana Department of Corrections. A quality assurance database of hepatitis C infected inmates evaluated in the Louisiana Department of Corrections was reviewed for liver biopsy and laboratory results. Patients were compared as to whether they would have been biopsied under the Federal Bureau of Prisons protocol and if there were histologic differences between those who would and those who would not have been biopsied. Of 490 inmates biopsied, 26% (129) had an alanine aminotransferase level between one and two times the upper limit of normal without other biochemical abnormalities. If treating stages 2-4, 48% of these would qualify for treatment (15% if treating stages 3-4). There was no statistical difference between this group and either the group with an alanine aminotransferase level between one and two times the upper limit of normal and with other laboratory abnormalities or the group with an alanine aminotransferase level greater than or equal to two times the upper limit of normal and without other abnormalities. In the Louisiana Department of Corrections, the Federal Bureau of Prisons protocol was neither sensitive nor specific enough at identifying those that should be considered for hepatitis C therapy.

This preclinical, phase 2 report shows that VX-445, a CFTR potentiator when administered with tezacaftor and ivacaftor, improved lung function and reduced sweat chloride concentrations and symptoms in patients harboring one or two Phe508del alleles.

This companion article to the VX-445 report shows that VX-659, a new CFTR potentiator, when administered with tezacaftor and ivacaftor improved lung function, sweat chloride concentration, and symptoms in patients with cystic fibrosis who harbored one or two Phe508del alleles.

In Pseudomonas aeruginosa the alp system encodes a programmed cell death pathway that is switched on in a subset of cells in response to DNA damage and is linked to the virulence of the organism. Here we show that the central regulator of this pathway, AlpA, exerts its effects by acting as an antiterminator rather than a transcription activator. In particular, we present evidence that AlpA positively regulates the alpBCDE cell lysis genes, as well as genes in a second newly identified target locus, by recognizing specific DNA sites within the promoter, then binding RNA polymerase directly and allowing it to bypass intrinsic terminators positioned downstream. AlpA thus functions in a mechanistically unusual manner to control the expression of virulence genes in this opportunistic pathogen. In Pseudomonas aeruginosa , the protein AlpA activates the expression of the alp locus in response to DNA damage, leading to lysis in a subset of cells and enhancing virulence of other, surviving cells. Here, the authors show that AlpA acts as an antiterminator rather than a transcriptional activator.

Although clinicians have traditionally used the Finnegan Neonatal Abstinence Scoring Tool to assess the severity of neonatal opioid withdrawal, a newer function-based approach - the Eat, Sleep, Console care approach - is increasing in use. Whether the new approach can safely reduce the time until infants are medically ready for discharge when it is applied broadly across diverse sites is unknown. In this cluster-randomized, controlled trial at 26 U.S. hospitals, we enrolled infants with neonatal opioid withdrawal syndrome who had been born at 36 weeks' gestation or more. At a randomly assigned time, hospitals transitioned from usual care that used the Finnegan tool to the Eat, Sleep, Console approach. During a 3-month transition period, staff members at each hospital were trained to use the new approach. The primary outcome was the time from birth until medical readiness for discharge as defined by the trial. Composite safety outcomes that were assessed during the first 3 months of postnatal age included in-hospital safety, unscheduled health care visits, and nonaccidental trauma or death. A total of 1305 infants were enrolled. In an intention-to-treat analysis that included 837 infants who met the trial definition for medical readiness for discharge, the number of days from birth until readiness for hospital discharge was 8.2 in the Eat, Sleep, Console group and 14.9 in the usual-care group (adjusted mean difference, 6.7 days; 95% confidence interval [CI], 4.7 to 8.8), for a rate ratio of 0.55 (95% CI, 0.46 to 0.65; P<0.001). The incidence of adverse outcomes was similar in the two groups. As compared with usual care, use of the Eat, Sleep, Console care approach significantly decreased the number of days until infants with neonatal opioid withdrawal syndrome were medically ready for discharge, without increasing specified adverse outcomes. (Funded by the Helping End Addiction Long-term (HEAL) Initiative of the National Institutes of Health; ESC-NOW ClinicalTrials.gov number, NCT04057820.).

Programmed cell death 1 (PD-1) is a premier cancer drug target for immune checkpoint blockade (ICB). Because PD-1 receptor inhibition activates tumor-specific T-cell immunity, research has predominantly focused on T-cell-PD-1 expression and its immunobiology. In contrast, cancer cell-intrinsic PD-1 functional regulation is not well understood. Here, we demonstrate induction of PD-1 in melanoma cells via type I interferon receptor (IFNAR) signaling and reversal of ICB efficacy through IFNAR pathway inhibition. Treatment of melanoma cells with IFN-α or IFN-β triggers IFNAR-mediated Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling, increases chromatin accessibility and resultant STAT1/2 and IFN regulatory factor 9 (IRF9) binding within a PD-1 gene enhancer, and leads to PD-1 induction. IFNAR1 or JAK/STAT inhibition suppresses melanoma-PD-1 expression and disrupts ICB efficacy in preclinical models. Our results uncover type I IFN-dependent regulation of cancer cell-PD-1 and provide mechanistic insight into the potential unintended ICB-neutralizing effects of widely used IFNAR1 and JAK inhibitors. Cancer cell-intrinsic PD-1 expression has been documented in multiple tumor types, including in melanoma. Here the authors identify a type I IFN-JAK/STAT signaling axis as a critical regulator of tumor cell-intrinsic PD-1 expression and targeting, with implications for cancer immunotherapy.

Elexacaftor–ivacaftor–tezacaftor therapy is efficacious in cystic fibrosis among patients with at least one copy of the Phe508del allele. In this trial involving patients with either a gating or residual function allele in addition to the Phe508del allele, elexacaftor–ivacaftor–tezacaftor improved lung function as compared with active control therapy.

Peptidylarginine deiminases (PAD1-4) are calcium dependent enzymes responsible for protein citrullination, a post-translational modification converting arginine residues to citrulline. Elevated levels of citrullinated proteins have been associated with rheumatoid arthritis, neurodegenerative diseases, and cancers. Though highly selective PAD4 inhibitors have been described, inhibitors to the broader family currently are limited to covalent substrate analogs. Herein, we describe an allosteric binding pocket common to PAD1-4 suitable for the identification of potent, non-covalent enzyme inhibitors. A ligand-based virtual screen is utilized to identify a PAD4 inhibitor for which surface plasmon resonance confirms target binding but non-competitively with a known PAD4 ligand. We further show through co-crystal structure analysis that the ligand binds PAD4 at an allosteric pocket resulting in stabilization of a catalytically inactive, calcium-deficient enzyme conformation. A ligand designed based on this site potently inhibits all four PAD isozymes and prevents protein citrullination in neutrophils with a broader protein repertoire than observed with a PAD4-selective inhibitor. Protein citrullination regulates the physiological function of proteins and is linked to various autoimmune disorders. Here, the authors report on the allosteric targeting of PAD1-4 leading to broad inhibition of protein citrullination in neutrophils.