Spiroplasma is a genus of Mollicutes whose members include plant pathogens, insect pathogens and endosymbionts of animals. Spiroplasma phenotypes have been repeatedly observed to be spontaneously lost in Drosophila cultures, and several studies have documented a high genomic turnover in Spiroplasma symbionts and plant pathogens. These observations suggest that Spiroplasma evolves quickly in comparison to other insect symbionts. Here, we systematically assess evolutionary rates and patterns of Spiroplasma poulsonii , a natural symbiont of Drosophila. We analysed genomic evolution of sHy within flies, and sMel within in vitro culture over several years. We observed that S. poulsonii substitution rates are among the highest reported for any bacteria, and around two orders of magnitude higher compared with other inherited arthropod endosymbionts. The absence of mismatch repair loci mutS and mutL is conserved across Spiroplasma , and likely contributes to elevated substitution rates. Further, the closely related strains sMel and sHy (>99.5 % sequence identity in shared loci) show extensive structural genomic differences, which potentially indicates a higher degree of host adaptation in sHy, a protective symbiont of Drosophila hydei. Finally, comparison across diverse Spiroplasma lineages confirms previous reports of dynamic evolution of toxins, and identifies loci similar to the male-killing toxin Spaid in several Spiroplasma lineages and other endosymbionts. Overall, our results highlight the peculiar nature of Spiroplasma genome evolution, which may explain unusual features of its evolutionary ecology.
SUMMARY Synaptic activity-induced calcium (Ca 2+ ) influx and subsequent propagation into the nucleus is a major way in which synapses communicate with the nucleus to regulate transcriptional programs important for activity-dependent survival and memory formation. Nuclear Ca 2+ shapes the transcriptome by regulating cyclic AMP (cAMP) response element-binding protein (CREB). Here, we utilize a Drosophila model of tauopathy and induced pluripotent stem cell (iPSC)-derived neurons from humans with Alzheimer’s disease to study the effects of pathogenic tau, a pathological hallmark of Alzheimer’s disease and related tauopathies, on nuclear Ca 2+ . We find that pathogenic tau depletes nuclear Ca 2+ and CREB to drive neuronal death, that CREB-regulated genes are over-represented among differentially expressed genes in tau transgenic Drosophila , and that activation of big potassium (BK) channels elevates nuclear Ca 2+ and suppresses tau-induced neurotoxicity. Our studies identify nuclear Ca 2+ depletion as a mechanism contributing to tau-induced neurotoxicity, adding an important dimension to the calcium hypothesis of Alzheimer’s disease.
Introduction While brains of patients with Alzheimer's disease and related tauopathies have evidence of altered RNA processing, we lack a mechanistic understanding of how altered RNA processing arises in these disorders and if such changes are causally linked to neurodegeneration. Methods Using Drosophila melanogaster models of tauopathy, we find that overall activity of nonsense‐mediated mRNA decay (NMD), a key RNA quality‐control mechanism, is reduced. Genetic manipulation of NMD machinery significantly modifies tau‐induced neurotoxicity, suggesting that deficits in NMD are causally linked to neurodegeneration. Mechanistically, we find that deficits in NMD are a consequence of aberrant RNA export and RNA accumulation within nuclear envelope invaginations in tauopathy. We identify a pharmacological activator of NMD that suppresses neurodegeneration in tau transgenic Drosophila, indicating that tau‐induced deficits in RNA quality control are druggable. Discussion Our studies suggest that NMD activators should be explored for their potential therapeutic value to patients with tauopathies.
We studied the immunohistochemical expression of HER-2/neu, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), estrogen receptor (ER), and progesterone receptor (PR) in uterine cervical small cell and large cell neuroendocrine carcinomas (SCNECs and LCNECs) from 24 patients seen at The University of Texas M.D. Anderson Cancer Center. The objectives were to determine their expression and prognostic role in survival. Twenty-three cases (95.8%) expressed VEGF. The tumors expressing EGFR, HER-2/neu, and COX-2 were modest in numbers: eight (33.3%), 10 (41.7%), and seven (29.2%), respectively. Only one tumor (4.2%) expressed ER, and only two tumors (8.3%) expressed PR. No significant differences in the expression of these factors were found between SCNECs and LCNECs or between stage I and stage II–III tumors. The median overall survival was 21.1 months (95% confidence interval [CI], 17.2–25.0 months). Only HER-2/neu expression was significantly associated with survival. Patients with negative HER-2/neu expression tumors had significantly shorter survival than those whose tumors were positive, 14.2 months (95% CI, 10.6−17.7 months) versus 33.1 months (95% CI, 0−76.92 months) (P = 0.03). There was a trend toward worse survival in patients with EGFR expression, but this finding was not significant. The combination of negative HER-2/neu expression and positive EGFR expression had the worst impact on survival.
Spiroplasma are a group of Mollicutes whose members include plant pathogens, insect pathogens, and endosymbionts of animals. In arthropods, Spiroplasma are found across a broad host range, but typically with lower incidence than other bacteria with similar ecology, such as Wolbachia or Rickettsia. Spiroplasma symbionts of Drosophila are best known as male-killers and protective symbionts, and both phenotypes are mediated by Spiroplasma-encoded toxins. Spiroplasma phenotypes have been repeatedly observed to be spontaneously lost in Drosophila cultures, and several studies have documented a high genomic turnover in Spiroplasma symbionts and plant pathogens. These observations suggest that Spiroplasma evolves quickly. Here, we systematically assess evolutionary rates and patterns of Spiroplasma poulsonii, a natural symbiont of Drosophila. We analysed genomic evolution of sHy within flies, and sMel within in vitro culture over several years. We observed that S. poulsonii substitution rates are among the highest reported for any bacteria, and markedly increased compared with other symbionts. The absence of mismatch repair loci mutS and mutL is conserved across Spiroplasma and likely contributes to elevated substitution rates. Further, the closely related strains sMel and sHy (>99.5% sequence identity in shared loci) show extensive structural genomic differences, which may be explained by a higher degree of host adaptation in sHy, a protective symbiont of Drosophila hydei. Finally, comparison across diverse Spiroplasma lineages confirms previous reports of dynamic evolution of toxins, and identifies loci similar to the male-killing toxin Spaid in several Spiroplasma lineages and other endosymbionts. Overall, our results highlight the peculiar nature of Spiroplasma genome evolution, which may explain unusual features of its evolutionary ecology.
Deposition of tau protein aggregates in the brain of affected individuals is a defining feature of “tauopathies,” including Alzheimer’s disease. Studies of human brain tissue and various model systems of tauopathy report that toxic forms of tau negatively affect nuclear and genomic architecture, identifying pathogenic tau–induced heterochromatin decondensation and consequent retrotransposon activation as a causal mediator of neurodegeneration. On the basis of their similarity to retroviruses, retrotransposons drive neuroinflammation via toxic intermediates, including double-stranded RNA (dsRNA). We find that dsRNA and dsRNA sensing machinery are elevated in astrocytes of postmortem brain tissue from patients with Alzheimer’s disease and progressive supranuclear palsy and in brains of tau transgenic mice. Using a Drosophila model of tauopathy, we identify specific tau-induced retrotransposons that form dsRNA and find that pathogenic tau and heterochromatin decondensation causally drive dsRNA-mediated neurodegeneration and neuroinflammation. Our study suggests that pathogenic tau–induced heterochromatin decondensation and retrotransposon activation cause elevation of inflammatory, transposable element–derived dsRNA in the adult brain.
The rate of groin breakdown after radical wide vulvar excision and inguinal lymphadenectomy for vulvar cancer remains significant despite conservative surgical approaches. An 86-year-old Latin American woman underwent wide radical excision and bilateral inguinal lymphadenectomy for vulvar cancer. The postoperative course was complicated by bilateral groin wound separation and high output lymphorrhea. The patient responded to the application of a gelatin matrix-thrombin tissue sealant (FloSeal®) to the bases of each groin with resolution in lymphorrhea and formation of granulation tissue. The application of a gelatin matrix-thrombin tissue sealant (FloSeal®) may be a viable treatment in the management of groin breakdown in selected patients when conventional therapy produces suboptimal results.
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