Autophagy is a process for the bulk degradation of proteins, in which cytoplasmic components of the cell are enclosed by double-membrane structures known as autophagosomes for delivery to lysosomes or vacuoles for degradation. This process is crucial for survival during starvation and cell differentiation. No molecules have been identified that are involved in autophagy in higher eukaryotes. We have isolated 14 autophagy-defective (apg) mutants of the yeast Saccharomyces cerevisiae and examined the autophagic process at the molecular level. We show here that a unique covalent-modification system is essential for autophagy to occur. The carboxy-terminal glycine residue of Apg12, a 186-amino-acid protein, is conjugated to a lysine at residue 149 of Apg5, a 294-amino-acid protein. Of the apg mutants, we found that apg7 and apg10 were unable to form an Apg5/Apg12 conjugate. By cloning APG7, we discovered that Apg7 is a ubiquitin-E1-like enzyme. This conjugation can be reconstituted in vitro and depends on ATP. To our knowledge, this is the first report of a protein unrelated to ubiquitin that uses a ubiquitination-like conjugation system. Furthermore, Apg5 and Apg12 have mammalian homologues, suggesting that this new modification system is conserved from yeast to mammalian cells.

The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biological, nonbiological, biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clinical products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic.

Salmonella typhimurium causes a localized enteric infection in immunocompetent individuals, whereas HIV-infected individuals develop a life-threatening bacteremia. Here we show that simian immunodeficiency virus (SIV) infection results in depletion of T helper type 17 (T H 17) cells in the ileal mucosa of rhesus macaques, thereby impairing mucosal barrier functions to S. typhimurium dissemination. In SIV-negative macaques, the gene expression profile induced by S. typhimurium in ligated ileal loops was dominated by T H 17 responses, including the expression of interleukin-17 (IL-17) and IL-22. T H 17 cells were markedly depleted in SIV-infected rhesus macaques, resulting in blunted T H 17 responses to S. typhimurium infection and increased bacterial dissemination. IL-17 receptor-deficient mice showed increased systemic dissemination of S. typhimurium from the gut, suggesting that IL-17 deficiency causes defects in mucosal barrier function. We conclude that SIV infection impairs the IL-17 axis, an arm of the mucosal immune response preventing systemic microbial dissemination from the gastrointestinal tract. A.G. served as consultant for the presentation of NTS bacteremia in African subjects. J.K.K. served as collaborator on studies with Il17ra −/− mice and provided useful comments on the experimental design. S.D. designed and supervised the SIV infections of rhesus macaques, blood sample scheduling, macaque protocols, processing and cell isolations for flow cytometry and DNA microarray analyses. A.J.B. was responsible for the experimental design and supervision of mouse studies, ligated ileal loop experiments in rhesus macaques, macaque protocols and analysis of host responses to Salmonella infection. A.J.B. collected tissue during the ligated ileal loop surgery and was responsible for the final manuscript preparation. A.J.B. and S.D. provided financial support for the study and equally contributed to the experimental design, supervision and data interpretation. Although nontyphoidal Salmonella serotypes (NTS) are common agents causing acute foodborne disease worldwide, it is unusual to isolate them from the blood of adults, because in immunocompetent individuals these pathogens remain localized to the intestine and cause a self-limiting gastroenteritis 1 . However, in people with underlying immunosuppression, NTS may spread beyond the intestine and reach the bloodstream, a serious complication known as NTS bacteremia2. The rise in the number of people with AIDS in sub-Saharan Africa has led to a dramatic increase in the frequency of NTS bacteremia3. In marked contrast to the pre-AIDS era4, NTS is currently a leading cause of hospital admission of adults and among the most common bacterial blood isolates from hospitalized adults in sub-Saharan Africa5, the vast majority of whom are HIV positive 3 . NTS infection in HIV-positive African adults is associated with high acute mortality rates (47%) 6 . Although the occurrence of NTS bacteremia in HIV-positive people is well documented, there are no reports inv...

SUMMARY Salmonella enterica serotype Typhimurium thrives in the lumen of the acutely inflamed intestine, which suggests that this pathogen is resistant to antimicrobials encountered in this environment. However, the identity of these antimicrobials and the corresponding bacterial resistance genes remains elusive. Here we show that enteric infection with S. Typhimurium evoked marked interleukin (IL)–22/IL-17 mediated induction in intestinal epithelial cells of lipocalin-2, an antimicrobial protein that prevents bacterial iron acquisition. Lipocalin-2 accumulated in the intestinal lumen of rhesus macaques during S. Typhimurium infection. Resistance to lipocalin-2, mediated by the iroBCDE iroN locus, conferred a competitive advantage upon the S. Typhimurium wild-type in colonizing the inflamed intestine of wild-type, but not of lipocalin-2 deficient mice. These data support that resistance to lipocalin-2 defines a specific adaptation to growth in the inflamed intestine.

Objective To develop updated guidelines for the pharmacologic management of rheumatoid arthritis. Methods We developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations. Results The guideline addresses treatment with disease‐modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high‐risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional). Conclusion This clinical practice guideline is intended to serve as a tool to support clinician and patient decision‐making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision‐making process based on patients’ values, goals, preferences, and comorbidities.