Interferon-α-induced mTOR activation is an anti-hepatitis C virus signal via the phosphatidylinositol 3-kinase-Akt-independent pathway

Object  The interferon-induced Jak-STAT signal alone is not sufficient to explain all the biological effects of IFN. The PI3-K pathways have emerged as a critical additional component of IFN-induced signaling. This study attempted to clarify that relationship between IFN-induced PI3-K-Akt-mTOR activity and anti-viral action. Result  When the human normal hepatocyte derived cell line was treated with rapamycin (rapa) before accretion of IFN-α, tyrosine phosphorylation of STAT-1 was diminished. Pretreatment of rapa had an inhibitory effect on the IFN-α-induced expression of PKR and p48 in a dose dependent manner. Rapa inhibited the IFN-α inducible IFN-stimulated regulatory element luciferase activity in a dose-dependent manner. However, wortmannin, LY294002 and Akt inhibitor did not influence IFN-α inducible luciferase activity. To examine the effect of PI3-K-Akt-mTOR on the anti-HCV action of IFN-α, the full-length HCV replication system, OR6 cells were used. The pretreatment of rapa attenuated its anti-HCV replication effect in comparison to IFN-α alone, whereas the pretreatment with PI3-K inhibitors, wortmannin and LY294002 and Akt inhibitor did not influence IFN-induced anti-HCV replication. Conclusion  IFN-induced mTOR activity, independent of PI3K and Akt, is the critical factor for its anti-HCV activity. Jak independent mTOR activity involved STAT-1 phosphorylation and nuclear location, and then PKR is expressed in hepatocytes.     

Paroxetine treatment of delusional disorder, somatic type

A 77-year-old female showed delusion of infestation in the oral cavity. She was treated by paroxetine 20 mg/day, and the hypochondriacal delusion disappeared after 8 weeks. Hypoperfusion in the left temporal and parietal lobes which was observed when she had the delusion was normalized after resolution of the delusion. This report suggests that paroxetine may be effective for delusional disorder, somatic type. It also supports the previous views that this disorder is associated with serotonergic dysfunction and hypoperfusion in the temporal and parietal lobes.     

TT virus-positive hepatocellular carcinoma arising from non-cirrhotic liver in an elderly man

A 43-mm hepatic tumor was incidentally detected by computed tomography in a 72-year-old man. Liver function test results were normal. Serum hepatitis B, C and G viruses were negative, while serum TT virus was positive. Autoantibodies were negative. The patient had no history of alcohol consumption. The tumor was found to be a moderately differentiated hepatocellular carcinoma (HCC) from a resected specimen. Neither lobular inflammation nor fibrosis was observed in the surrounding liver. Intrahepatic hepatitis B virus was not detected. This is a case of non-B, non-C HCC positive for only TT virus arising from a non-cirrhotic liver.     

Frequent loss of heterozygosity at telomeric loci on 22q in sporadic colorectal cancers

To date, several tumor-suppressor genes responsible for the tumorigenesis of colorectal cancer have been identified. However, studies of loss of heterozygosity (LOH) have suggested several chromosomal regions which may contain additional tumor-suppressor genes for colorectal cancer. To determine the extent and variation of allelic loss on 22q, on which LOH has been frequently observed, a total of 68 sporadic colorectal cancers was examined for LOH on the chromosome arm by means of 16 polymorphic DNA markers. LOH was observed in 28 tumors (41 %), of which 9 showed LOH at all informative loci. The remaining 19 tumors showed variable patterns of partial loss on 22q, delimiting the smallest region of overlap (SRO) between D22S90 and D22S94. Moreover, LOH within the SRO correlated with a progression in terms of Dukes' stages. These results suggest that an additional tumor-suppressor gene for colorectal cancer may exist on 22q distally to the NF2 locus and that inactivation of the gene may possibly play a role in the progression or metastasis of colorectal cancers. © 1995 Wiley-Liss, Inc.     

Infectious Retrovirus Is Inactivated by Serum but Not by Cerebrospinal Fluid or Fluid from Tumor Bed in Patients with Malignant Glioma

Intravenous gene transfer using recombinant retroviruses tends to suffer from a low infectious viral titer when conducted in vivo. This is, in part, caused by complement-mediated proteolytic inactivation of the retrovirus in human serum. However, if the retroviruses were directly injected into the brain, they might not be inactivated. Supernatant from amphotropic retrovirus-producing cells harboring the BAG vectors was incubated with sera or cerebrospinal fluid (CSF) of patients with gliomas or unrelated disorders. The retroviruses were severely inactivated in sera. However, no such inactivation was noted in CSF or fluid from the tumor bed of glioma patients. These data suggest that gene transfer using recombinant retroviruses could be done into the cavity after removal of the tumor in glioma patients.     

Antagonistic and agonistic effects of an extracellular fragment of nectin on formation of E-cadherin-based cell-cell adhesion

BACKGROUND: Nectin is a Ca2+-independent immunoglobulin-like cell-cell adhesion molecule at the E-cadherin-based cell-cell adherens junctions (AJs), and comprises a family consisting of four members, nectin-1, -2, -3, and -4. Nectin and E-cadherin are associated with afadin and alpha-catenin, actin filament (F-actin)-binding proteins connecting respective adhesion molecules to the actin cytoskeleton, but the role of nectin in the formation of the E-cadherin-based cell-cell AJs has not yet been fully understood. To obtain evidence for this role of nectin, we attempted to develop an antagonist and/or agonist of nectin. RESULTS: We made a recombinant extracellular fragment of nectin-3 (Nef-3). Nef-3 trans-interacted with cellular nectin-1 and thereby diminished the formation of the nectin-1-based cell-cell adhesion. This resulted in a reduction of the formation of the E-cadherin-based cell-cell adhesion in L fibroblasts stably expressing both exogenous nectin-1alpha and E-cadherin (nectin-1-EL cells) and MDCK cells stably expressing exogenous nectin-1alpha (nectin-1-MDCK cells). This antagonistic effect of Nef-3 was also observed in L cells stably expressing exogenous E-cadherin alone (EL cells) and wild-type MDCK cells. Conversely, Nef-3 coated on microbeads first recruited the nectin-afadin complex and then the E-cadherin-catenin complex to the bead-cell contact sites in nectin-1-EL and nectin-1-MDCK cells. CONCLUSION: These results suggest that nectin is necessary and sufficient for the recruitment of E-cadherin to the nectin-based cell-cell adhesion sites and involved in the formation of E-cadherin-based cell-cell AJs.     

Dynamics of Political Polarization Special Feature: Interindividual cooperation mediated by partisanship complicates Madison’s cure for “mischiefs of faction”

Political theorists have long argued that enlarging the political sphere to include a greater diversity of interests would cure the ills of factions in a pluralistic society. While the scope of politics has expanded dramatically over the past 75 y, polarization is markedly worse. Motivated by this paradox, we take a bottom–up approach to explore how partisan individual-level dynamics in a diverse (multidimensional) issue space can shape collective-level factionalization via an emergent dimensionality reduction. We extend a model of cultural evolution grounded in evolutionary game theory, in which individuals accumulate benefits through pairwise interactions and imitate (or learn) the strategies of successful others. The degree of partisanship determines the likelihood of learning from individuals of the opposite party. This approach captures the coupling between individual behavior, partisan-mediated opinion dynamics, and an interaction network that changes endogenously according to the evolving interests of individuals. We find that while expanding the diversity of interests can indeed improve both individual and collective outcomes, increasingly high partisan bias promotes a reduction in issue dimensionality via party-based assortment that leads to increasing polarization. When party bias becomes extreme, it also boosts interindividual cooperation, thereby further entrenching extreme polarization and creating a tug-of-war between individual cooperation and societal cohesion. These dangers of extreme partisanship are highest when individuals’ interests and opinions are heavily shaped by peers and there is little independent exploration. Overall, our findings highlight the urgency to study polarization in a coupled, multilevel context.

Two hundred and twenty-five years ago, George Washington, in his farewell address, predicted that factions—or monolithic parties—would yield precisely the political sectarianism that the United States now experiences. As party sectarianism has increased, democratic norms have eroded, and the United States seems to be at a breaking point. However, a decade prior to Washington’s speech, James Madison argued that the “mischiefs of faction” could be prevented by expanding the sphere of politics: In a society with diverse interests, no faction could act as a monolith and agendas could be pursued only by negotiating across differences and forming alliances toward shared goals.The scope of politics has dramatically increased over the past 75 y. Potentially driven by increases in educational attainment, the nationalization of politics, and changes to the information environment (1, 2), the number of issues people care about and consider within the realm of national politics has markedly increased (3–5). Despite this trend, and the consequent expectation that an abundance of issues will improve the collective cohesion by decreasing the likelihood of monoliths, polarization is markedly worse.A potential explanation for this paradox is the decreasing dimensionality of the issue space. In other words, although the number of issues may have increased, individuals’ opinions on these issues might be so strongly correlated with their political ideology that, in effect, there are only one or two issue dimensions (6, 7). While some papers have argued that the decreasing dimensionality of issue attitudes (8, 9) is at the core of current political tensions, any demonstrated relationship between dimensionality reduction and polarization has been merely correlational. In fact, some have argued that “[a]lthough polarization and the reduction in dimensionality tend to coincide, there is no necessary logical connection between the two trends” (ref. 10, p. 42).Here we propose a bottom–up mechanism that might offer a resolution for the paradox of polarization in the face of rising issue diversity. In particular, we focus on individual-level interactions that are influenced by issue stances, coupled with social learning that is mediated by partisan bias. The issues individuals care about (political or otherwise) and the stances they take on these issues have become both increasingly visible to others (e.g., via social media) and strong determinants of individual behaviors (11): How trustful, forgiving, or helpful we are—even in quotidian, pairwise interactions with neighbors, colleagues, friends, or strangers (12–15)—can hinge on our respective views on a variety of issues, from preferred sports teams to art tastes (16) to gun control or to favored political candidates [even in a primary election (12)]. Simultaneously, the stronger the perceived partisan bias, the less likely it is that individuals leaning toward one end of the political spectrum will embrace issues or opinions held by those at the opposite end (e.g., mask wearing in the COVID-19 pandemic) (17–19).We propose that the interplay between individual-level behavior on the one hand and the degree of partisanship on the other hand mediates the effect of issue dimensionality both on individual-level dynamics and on emergent collective-level factioning. To investigate this proposition, we extend an evolutionary game theoretic (20, 21) model of cultural evolution (22) that allows the coevolution of individual states and social networks (23): Individuals imitate others—i.e., adopt their interests, opinions, and strategies—depending on their relative success in a pairwise donation game (also known as a simplified Prisoner’s Dilemma). Our choice of game is motivated by previous behavioral studies that have used similar pairwise games, such as the dictator game or the trust game, to measure cooperation between individuals with different political or other attitudes (12–15). However, our framework is sufficiently versatile to allow multiplayer interactions, such as public goods games, or even multilevel interactions, in which individuals can not only cooperate with peers but also contribute to their party.Finally, but importantly, we assume that the imitation process is influenced by political affiliations and partisan bias, a mesolevel societal organization—intermediate between the individual and the collective—that governs the extent of a politically mediated reduction in issue dimensionality (24). Because we focus on the United States, where third parties have minimal influence (25), we model a two-party system (L, R) with individuals distributed equally between the parties. We also ignore unaffiliated independents since a majority of independents admit to leaning Democrat or Republican and act much like their partisan counterparts, at least in their voting behavior (26). However, because independents may perceive partisan bias differently in their day-to-day pairwise interactions, future work should extend this model to consider an independent class.     

An Investigation on Sleep Disturbance of Autistic Children

Abstract: For the purpose of clarifying the pathophysiological meaning of sleep disturbance in autistic children, the sleep pattern of 75 such children was examined by a questionnaire method. Forty-nine of them showed sleep disturbance in their early life with an incidence of 65%. The poorly-developed group showed a high rate of sleep disturbance as compared with the relatively well-developed group. There was a negative correlation between the developmental level and duration period of sleep disturbance. The investigation of circumstances in which autistic children often exhibited sleep disturbance proved that abrupt changes in life environment or various problems in the way of bringing up children brought about their sleep disturbance. These findings suggest that sleep disturbance might be one of the main symptoms and related to the pathophysiology of infantile autism.     

Clinical Features of Autistic Children with Setback Course in Their Infancy

Abstract: This study examines the incidence rate of setback in 80 autistic children, the correlation between the type of onset and clinical features, developmental level and prognosis based on an originally developed questionnaire. Moreover, this study seeks to investigate the possibility that infantile autism might be classified into subgroups by the type of onset.

• 1) The acquired (including questionably acquired) group consisted of 39 cases (49%), while the natal group was made up of 41 cases (51%).
• 2) The age when the setback occurred was 21–22 months in the acquired group.
• 3) Precipitating psychological events were observed in 22 cases (56%) of the acquired group.
• 4) The mental developmental level including speech and sociability function at 5 years of age was significantly lower in the acquired group than in the natal group.
• 5) The acquired group showed severe behavioral disorderssuch as “stereotypic behavior,”“extremely hyperkinetic behavior” and “self-abusive behavior” compared with the natal group.
• 6) The adaptive levels at schools or institutions were lower in the acquired group than in the natal group.
• 7) There was a higher incidence of epileptic seizures orfebrile convulsions in the acquired group than in the natal group. Moreover, there was a higher incidence of severe perinatal abnormalities in the acquired group.
• 8) The above-mentioned results suggest that infantile autism might be classified into two subgroups, acquired and natal groups, based on the typeof onset, and also suggest that some types of brain dysfunctions are more severe in the acquired group than in the natal group.