Deep Characterization of the Human Antibody Response to Natural Infection Using Longitudinal Immune Repertoire Sequencing.

Human antibody response studies are largely restricted to periods of high immune activity (e.g. vaccination). To comprehensively understand the healthy B cell immune repertoire and how this changes over time and through natural infection, we conducted immune repertoire RNA sequencing on flow cytometry-sorted B cell subsets to profile a single individual's antibodies over 11 months through two periods of natural viral infection. We found that 1) a baseline of healthy variable (V) gene usage in antibodies exists and is stable over time, but antibodies in memory cells consistently have a different usage profile relative to earlier B cell stages; 2) a single complementarity-determining region 3 (CDR3) is potentially generated from more than one VJ gene combination; and 3) IgG and IgA antibody transcripts are found at low levels in early human B cell development, suggesting that class switching may occur earlier than previously realized. These findings provide insight into immune repertoire stability, response to natural infections, and human B cell development.

Syrbactin class proteasome inhibitor-induced apoptosis and autophagy occurs in association with p53 accumulation and Akt/PKB activation in neuroblastoma.

Syrbactins belong to a new class of proteasome inhibitors which include syringolins and glidobactins. These small molecules are structurally distinct from other, well-established proteasome inhibitors, and bind the eukaryotic 20S proteasome by a novel mechanism. In this study, we examined the effects of syringolin A (SylA) and glidobactin A (GlbA) as well as two synthetic SylA-analogs (SylA-PEG and SylA-LIP) in human neuroblastoma (SK-N-SH), human multiple myeloma (MM1.S, MM1.RL, and U266), and human ovarian cancer (SKOV-3) cells. While all four syrbactins inhibited cell proliferation in a dose-dependent manner, GlbA was most potent in both dexamethasone-sensitive MM1.S cells (IC(50): 0.004microM) and dexamethasone-resistant MM1.RL cells (IC(50): 0.005microM). Syrbactins also inhibited the chymotrypsin-like proteasome activity in a dose-dependent fashion, and GlbA was most effective in SK-N-SH cells (IC(50): 0.015microM). The GlbA-promoted inhibition of proteasomal activity in SK-N-SH cells resulted in the accumulation of ubiquitinated proteins and tumor suppressor protein p53 and led to apoptotic cell death in a time-dependent manner. GlbA treatment also promoted the activation of Akt/PKB via phosphorylation at residue Ser(473) and induced autophagy as judged by the presence of the lipidated form of microtubule-associated protein 1 light chain 3 (LC3) and autophagosomes. Collectively, our data suggest that syrbactins belong to a new and effective proteasome inhibitor class which promotes cell death. Proteasome inhibition is a promising strategy for targeted anticancer therapy and syrbactins are a new class of inhibitors which provide a structural platform for the development of novel, proteasome inhibitor-based drug therapeutics.

Sudden death due to nontraumatic diaphragmatic hernia in an adult.

Sudden death in an adult due to an undiagnosed congenital diaphragmatic hernia (CDH) is a very rare occurrence. The majority of adults who experience discomfort related to their condition have experienced some kind of trauma prior to symptom manifestation; however, there can be the cases that are exceptions to a medical trend. In the following, we present a case of an adult female who died from an undiagnosed congenital diaphragmatic hernia without any prior traumatic event or significant medical history. In these situations, early diagnosis and rapid surgical intervention are necessary for successful treatment of affected individuals.

Cracking the code: a decode strategy for the international business machines punch cards of Korean war soldiers.

During the Korean War, International Business Machines (IBM) punch cards were created for every individual involved in military combat. Each card contained all pertinent personal information about the individual and was utilized to keep track of all soldiers involved. However, at present, all of the information known about these punch cards reveals only their format and their significance; there is little to no information on how these cards were created or how to interpret the information contained without the aid of the computer system used during the war. Today, it is believed there is no one available to explain this computerized system, nor do the original computers exist. This decode strategy is the result of an attempt to decipher the information on these cards through the use of all available medical and dental records for each individual examined. By cross-referencing the relevant personal information with the known format of the cards, a basic guess-and-check method was utilized. After examining hundreds of IBM punch cards, however, it has become clear that the punch card method of recording information was not infallible. In some cases, there are gaps of information on cards where there are data recorded on personal records; in others, information is punched incorrectly onto the cards, perhaps as the result of a transcription error. Taken all together, it is clear that the information contained on each individual's card should be taken solely as another form of personal documentation.