A proliferation-inducing ligand sustains the proliferation of human naïve (CD27−) B cells and mediates their differentiation into long-lived plasma cells in vitro via transmembrane activator and calcium modulator and cyclophilin ligand interactor and B-cell mature antigen

AbstractLong-lived plasma cells (PCs) contribute to humoral immunity through an undefined mechanism. Memory B cells, but not human naïve B cells, can be induced to differentiate into long-lived PCs in vitro. Because evidence links a proliferation-inducing ligand (APRIL), a tumor necrosis factor family member, to the ability of bone marrow to mediate long-term PC survival, we reasoned that APRIL influences the proliferation and differentiation of naïve B cells. We describe here the development of a simple cell culture system that allowed us to show that APRIL sustained the proliferation of naïve human B cells and induced them to differentiate into long-lived PCs. Blocking the transmembrane activator and calcium modulator and cyclophilin ligand interactor or B-cell mature antigen shows they were required for the differentiation of naïve B cells into long-lived PCs in vitro. Our in vitro culture system will reveal new insights into the biology of long-lived PCs

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas that recurred as a ductal adenocarcinoma likely via intraductal spread: A case report and review of the literature

It is hypothesized that cells of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas can move through the pancreatic duct and seed to form a new tumor (intraductal spread). Although this hypothesis typically refers to recurrent IPMNs in the remnant pancreas of patients who underwent operation for IPMN, studies providing sufficient evidence to prove this hypothesis are limited. Furthermore, if pancreatic ductal adenocarcinoma (PDAC) occurs in the remnant pancreas of patients who underwent complete resection for IPMN, any recurrence of PDAC with no associated IPMN is generally considered independent of prior IPMN. Here, we present a case of a minimally invasive IPMN occurring in the head of the pancreas that recurred as a PDAC in the tail of the pancreas ten years after the first operation for IPMN, likely via intraductal spread. Although the IPMN was surgically resected with negative margins and the recurrent adenocarcinoma did not accompany an IPMN, we found that both lesions shared an exceedingly rare KRAS mutation (p.A11delinsGGGV). Furthermore, we identified a microscopic, low-grade intraepithelial lesion in the main pancreatic duct adjacent to the adenocarcinoma that also harbored the same KRAS mutation. Immunohistochemically, the intraepithelial lesion retained SMAD4 expression, whereas the recurrent adenocarcinoma showed loss of SMAD4 expression, indicating that the intraepithelial lesion was a pancreatic intraepithelial neoplasia (PanIN) rather than adenocarcinoma (cancerization of the duct). These findings suggested that the initial IPMN, recurrent adenocarcinoma, and PanIN were clonally related, and intraductal spread of precursor neoplastic cells may have played a role in developing the adenocarcinoma. This case provides new insight into the process of how metachronous PDAC occurs in patients who undergo complete resection for IPMN

Suppression of Viral Replication by Stress-Inducible GADD34 Protein via the Mammalian Serine/Threonine Protein Kinase mTOR Pathway▿

GADD34 is a protein that is induced by a variety of stressors, including DNA damage, heat shock, nutrient deprivation, energy depletion, and endoplasmic reticulum stress. Here, we demonstrated that GADD34 induced by vesicular stomatitis virus (VSV) infection suppressed viral replication in wild-type (WT) mouse embryo fibroblasts (MEFs), whereas replication was enhanced in GADD34-deficient (GADD34-KO) MEFs. Enhanced viral replication in GADD34-KO MEFs was reduced by retroviral gene rescue of GADD34. The level of VSV protein expression in GADD34-KO MEFs was significantly higher than that in WT MEFs. Neither phosphorylation of eIF2α nor cellular protein synthesis was correlated with viral replication in GADD34-KO MEFs. On the other hand, phosphorylation of S6 and 4EBP1, proteins downstream of mTOR, was suppressed by VSV infection in WT MEFs but not in GADD34-KO MEFs. GADD34 was able to associate with TSC1/2 and dephosphorylate TSC2 at Thr1462. VSV replication was higher in TSC2-null cells than in TSC2-expressing cells, and constitutively active Akt enhanced VSV replication. On the other hand, rapamycin, an mTOR inhibitor, significantly suppressed VSV replication in GADD34-KO MEFs. These findings demonstrate that GADD34 induced by VSV infection suppresses viral replication via mTOR pathway inhibition, indicating that cross talk between stress-inducible GADD34 and the mTOR signaling pathway plays a critical role in antiviral defense

Terorisme kontemporer dunia Islam

This study is inspired by the problem of claims against terrorism as an expression of momentary interest, activities program, and products of history constructivism. To solve such problem, the study uses a critical historical analysis approach of Karl Rudolf Bultmann. The study concludes that terrorism, as a part of the wholeness of history, has played critical roles, namely the control role to the tyrannical-dominance and the role of ideology actualization. With the provision of institutionalized historical legacy, terrorism is not merely a temporary expression but it penetrates into borders of period of the history. In addition, with an emphasis on problem solving at the contemporary era, terrorism action is charged to provide a momentary response. Conceptual sources of this study are the view of Ahmad Jainuri about the character of terrorism and the view of Diniesh D’Souza on the profile and the main motive of terrorism. Based on evidences, data, and discussions of experts as well the terror doers themselves, the author argues that the essential meaning of terror—as a compelled action—lays in the fact that it is a noble meaning of historical and ideological aspects as well as a transcendent honor, which cross over the boundary of all conditions or all kinds of worldly reward

Concomitant drugs at baseline.

<p>Concomitant drugs at baseline.</p

Percentage change in the urinary albumin-to-creatinine ratio.

<p>Percentage change in the urinary albumin-to-creatinine ratio.</p