PPARγagonists can either enhance or inhibit eosinophil migration, which is a sum of directional migration (chemotaxis) and random cell movement (chemokinesis). To date, the effects of PPAR agonists on chemokinesis have not been examined. This study investigates the effects of PPARα,δ, andγagonists on eosinophil migration and chemokinesis. Eosinophils purified from blood of atopic donors were preincubated with rosiglitazone (PPARγagonist), GW9578 (PPARαagonist), GW501516 (PPARδagonist), or diluent. The effects of PPAR agonists were examined on eosinophil chemokinesis, eotaxin-induced migration of eosinophils, and migration of IL-5Rα+ CD34+ cells. Expressions of CCR3, phospho-p38, phospho-ERK, and calcium release were also measured in eosinophils after rosiglitazone treatment. Low concentrations of rosiglitazone, but not GW9578 or GW501516, increased chemokinesis of eosinophils (P=0.0038), and SDF-1α-induced migration of immature eosinophils (P=0.0538). Rosiglitazone had an effect on eosinophil calcium flux but had no effect on expression of CCR3 or phosphorylation of p38 or ERK. In contrast, high concentrations of rosiglitazone inhibited eosinophil migration (P=0.0042). The effect of rosiglitazone on eosinophil migration and chemokinesis appears to be through modification of calcium signaling, which alludes to a novel PPAR-mediated mechanism to modulate eosinophil function.

Prion-like self-perpetuating conformational conversion of proteins into amyloid aggregates is associated with both transmissible neurodegenerative diseases and non-Mendelian inheritance. Here, we demonstrate that ATP modulates the formation and dissolution of amyloids from a yeast prion domain (NM domain of Saccharomyces cerevisiae Sup35) and restricts autocatalytic amplification by controlling the amount of fragmentable and seeding-competent aggregates. ATP, at (high) physiological concentrations in the presence of Mg2+, kinetically accelerates NM aggregation. Interestingly, ATP also promotes phase-separation-mediated aggregation of a human protein harboring a yeast prion-like domain. We also show that ATP dose independently disaggregates preformed NM fibrils. Furthermore, high concentrations of ATP delimited the number of seeds by generating compact, ATP-bound NM fibrils that exhibited nominal fragmentation by either free ATP or Hsp104 disaggregase. Additionally, (low) pathological ATP concentrations restricted autocatalytic amplification by forming structurally distinct seeding-inefficient amyloids. Our results provide mechanistic underpinnings of concentration-dependent chemical chaperoning by ATP against prion-like transmissions.

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Gurdial Singh’s first novel Marhi Da Deeva (1964) is one of his most famous novels. Retrospectively, it is considered the first dalit novel in Punjabi. It has acquired the status of a classic in Punjabi fiction. Apart from being translated in many Indian languages, it has been translated in Russian; the version selling ten lac copies. The movie version of the novel, produced in Hindi and Punjabi by National Film Development Corporation was critically much acclaimed. It bagged the best regional feature film award in 1990. Jagseer, the protagonist of the novel, was hailed as the first dalit hero in Punjabi fiction. Here, one is tempted to place the novel within the corpus of dalit writings. But, as is argues here, the text does not support such a reading. Whatever comes up during the course of the novel is only authentic experience. This authenticity is best understood if we compare this novel with Samskara. One readily realizes that Samskara lacks any direct negotiation with the reality. It is rather a distanced vision. The novelist ends up talking about himself rather than the society. Marhi Da Deeva, however, stems from direct experience.