Convergence and divergence in the evolution of cat skulls: temporal and spatial patterns of morphological diversity

Background: Studies of biological shape evolution are greatly enhanced when framed in a phylogenetic perspective. Inclusion of fossils amplifies the scope of macroevolutionary research, offers a deep-time perspective on tempo and mode of radiations, and elucidates life-trait changes. We explore the evolution of skull shape in felids (cats) through morphometric analyses of linear variables, phylogenetic comparative methods, and a new cladistic study of saber-toothed cats. Methodology/Principal Findings: A new phylogenetic analysis supports the monophyly of saber-toothed cats (Machairodontinae) exclusive of Felinae and some basal felids, but does not support the monophyly of various sabertoothed tribes and genera. We quantified skull shape variation in 34 extant and 18 extinct species using size-adjusted linear variables. These distinguish taxonomic group membership with high accuracy. Patterns of morphospace occupation are consistent with previous analyses, for example, in showing a size gradient along the primary axis of shape variation and a separation between large and small-medium cats. By combining the new phylogeny with a molecular tree of extant Felinae, we built a chronophylomorphospace (a phylogeny superimposed onto a two-dimensional morphospace through time). The evolutionary history of cats was characterized by two major episodes of morphological divergence, one marking the separation between saber-toothed and modern cats, the other marking the split between large and small-medium cats. Conclusions/Significance: Ancestors of large cats in the ‘Panthera’ lineage tend to occupy, at a much later stage, morphospace regions previously occupied by saber-toothed cats. The latter radiated out into new morphospace regions peripheral to those of extant large cats. The separation between large and small-medium cats was marked by considerable morphologically divergent trajectories early in feline evolution. A chronophylomorphospace has wider applications in reconstructing temporal transitions across two-dimensional trait spaces, can be used in ecophenotypical and functional diversity studies, and may reveal novel patterns of morphospace occupation

Successful treatment of recurrent small bowel adenocarcinoma by cytoreductive surgery and chemotherapy: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Small bowel adenocarcinoma is a rare malignancy associated with a poor prognosis and there is little evidence of effective treatment. Recurrent small bowel adenocarcinoma is an intractable disease for which there is little information available regarding its treatment by palliative therapy. We present a case of recurrent small bowel adenocarcinoma successfully treated by cytoreductive surgery and palliative chemotherapy.</p> <p>Case presentation</p> <p>We report the case of a 72-year-old Japanese female who developed a peritoneal metastasis from recurrent small bowel adenocarcinoma after curative resection and adjuvant chemotherapy with S-1 and polysaccharide K. She underwent cytoreductive surgery followed by chemotherapy with folinic acid/fluorouracil/oxaliplatin and folinic acid/fluorouracil/irinotecan with polysaccharide K. Subsequently, no sign of a recurrence was observed 42 months after the second operation.</p> <p>Conclusion</p> <p>To the best of our knowledge, this is the first case report of the successful treatment of peritoneal metastasis from small bowel adenocarcinoma by cytoreductive surgery and combination chemotherapy (folinic acid/fluorouracil/oxaliplatin and folinic acid/fluorouracil/irinotecan with polysaccharide K).</p

The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver

LKB1 is a master kinase that regulates metabolism and growth through adenosine monophosphate-activated protein kinase (AMPK) and 12 other closely related kinases. Liver-specific ablation of LKB1 causes increased glucose production in hepatocytes in vitro and hyperglycaemia in fasting mice in vivo. Here we report that the salt-inducible kinases (SIK1, 2 and 3), members of the AMPK-related kinase family, play a key role as gluconeogenic suppressors downstream of LKB1 in the liver. The selective SIK inhibitor HG-9-91-01 promotes dephosphorylation of transcriptional co-activators CRTC2/3 resulting in enhanced gluconeogenic gene expression and glucose production in hepatocytes, an effect that is abolished when an HG-9-91-01-insensitive mutant SIK is introduced or LKB1 is ablated. Although SIK2 was proposed as a key regulator of insulin-mediated suppression of gluconeogenesis, we provide genetic evidence that liver-specific ablation of SIK2 alone has no effect on gluconeogenesis and insulin does not modulate SIK2 phosphorylation or activity. Collectively, we demonstrate that the LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver

Mutation analysis of the Gadd45 gene at exon 4 in atypical fibroxanthoma

<p>Abstract</p> <p>Background</p> <p>Atypical fibroxanthoma (AFX) histologically mimics high-grade sarcoma in the skin, although it follows a benign clinical course. AFX occurs in the sun-exposed skin and for this reason, an association with ultraviolet light has long been suspected. Bax and Gadd45 are p53 effector proteins. Bax is a programmed cell death protein and belongs to the Bcl-2 family. Gadd45 is a multifunctional DNA damage-inducible gene associated with the process of DNA damage.</p> <p>Methods</p> <p>Immunohistochemical expression of Bax was analyzed in 7 cases of AFX, and in 7 cases of benign fibrous histiocytoma (BFH) used as a comparison. The expression pattern of Bax was compared to previously reported p53 and Gadd45 expressions in a correspondent series. Mutation of the Gadd45 gene at exon 4 was also analyzed in AFX.</p> <p>Results</p> <p>AFX and BFH showed immunoreactivities respectively for Bax (3/7, 0/7), Gadd45 (4/7, 1/7) and p53 (2/7, 0/7). There was no exact correlation between p53 expression and Bax or Gadd45 expression. However, the pattern of expression between Bax and Gadd45 was also the same, with the exception of one case. No mutation of the Gadd45 gene at exon 4 was observed in a series of 6 AFX cases where DNA was available (0/6).</p> <p>Conclusion</p> <p>These results suggest a possible association between Bax and Gadd45 in AFX, and may refute any possibility of dysfunction of Gadd45 in terms of gene mutation, at least at exon 4 of the Gadd45 gene.</p

Second primary squamous cell carcinoma arising in cutaneous flap reconstructions of two head and neck cancer patients

Early complications of myocutaneous flap transfers following surgical eradication of head and neck tumors have been extensively described. However, knowledge concerning long-term complications of these techniques remains limited. We report the cases of two patients with a prior history of squamous cell carcinoma of the head and neck (HNSCC), who developed a second primary SCC on the cutaneous surface of their flaps, years after reconstruction. Interestingly, it seems that the well-known risk of a second primary SCC in patients with previous head and neck carcinoma also applies to foreign tissues implanted within the area at risk. Given the important expansion of these interventions, this type of complication may become more frequent in the future. Therefore, long-term follow-up of patients previously treated for HNSCC not only requires careful evaluation of the normal mucosa of the upper aero-digestive tract, but also of the cutaneous surface of the flap used for reconstruction

Dynamics of dental evolution in ornithopod dinosaurs.

Ornithopods were key herbivorous dinosaurs in Mesozoic terrestrial ecosystems, with a variety of tooth morphologies. Several clades, especially the 'duck-billed' hadrosaurids, became hugely diverse and abundant almost worldwide. Yet their evolutionary dynamics have been disputed, particularly whether they diversified in response to events in plant evolution. Here we focus on their remarkable dietary adaptations, using tooth and jaw characters to examine changes in dental disparity and evolutionary rate. Ornithopods explored different areas of dental morphospace throughout their evolution, showing a long-term expansion. There were four major evolutionary rate increases, the first among basal iguanodontians in the Middle-Late Jurassic, and the three others among the Hadrosauridae, above and below the split of their two major clades, in the middle of the Late Cretaceous. These evolutionary bursts do not correspond to times of plant diversification, including the radiation of the flowering plants, and suggest that dental innovation rather than coevolution with major plant clades was a major driver in ornithopod evolution

Adenosine A2A receptor modulation of hippocampal CA3-CA1 synapse plasticity during associative learning in behaving mice

© 2009 Nature Publishing Group All rights reservedPrevious in vitro studies have characterized the electrophysiological and molecular signaling pathways of adenosine tonic modulation on long-lasting synaptic plasticity events, particularly for hippocampal long-term potentiation(LTP). However, it remains to be elucidated whether the long-term changes produced by endogenous adenosine in the efficiency of synapses are related to those required for learning and memory formation. Our goal was to understand how endogenous activation of adenosine excitatory A2A receptors modulates the associative learning evolution in conscious behaving mice. We have studied here the effects of the application of a highly selective A2A receptor antagonist, SCH58261, upon a well-known associative learning paradigm - classical eyeblink conditioning. We used a trace paradigm, with a tone as the conditioned stimulus (CS) and an electric shock presented to the supraorbital nerve as the unconditioned stimulus(US). A single electrical pulse was presented to the Schaffer collateral–commissural pathway to evoke field EPSPs (fEPSPs) in the pyramidal CA1 area during the CS–US interval. In vehicle-injected animals, there was a progressive increase in the percentage of conditioning responses (CRs) and in the slope of fEPSPs through conditioning sessions, an effect that was completely prevented (and lost) in SCH58261 (0.5 mg/kg, i.p.)-injected animals. Moreover, experimentally evoked LTP was impaired in SCH58261- injected mice. In conclusion, the endogenous activation of adenosine A2A receptors plays a pivotal effect on the associative learning process and its relevant hippocampal circuits, including activity-dependent changes at the CA3-CA1 synapse.This study was supported by grants from the Spanish Ministry of Education and Research (BFU2005-01024 and BFU2005-02512), Spanish Junta de Andalucía (BIO-122 and CVI-02487), and the Fundación Conocimiento y Cultura of the Pablo de Olavide University (Seville, Spain).B. Fontinha was in receipt of a studentship from a project grant (POCI/SAU-NEU/56332/2004) supported by Fundação para a Ciência e Tecnologia (FCT, Portugal), and of an STSM from Cost B30 concerted action of the EU

Thoracoscopic detection of occult indeterminate pulmonary nodules using bronchoscopic pleural dye marking

Background: The annual incidence of a small indeterminate pulmonary nodule (IPN) on computed tomography (CT) scan remains high. While traditional paradigms exist, the integration of new technologies into these diagnostic and treatment algorithms can result in alternative, potentially more efficient methods of managing these findings. Methods: We report on an alternative diagnostic and therapeutic strategy for the management of an IPN. This approach combines electromagnetic navigational bronchoscopy (ENB) with an updated approach to placement of a pleural dye marker. This technique lends itself to a minimally invasive wedge resection via either video-assisted thoracoscopic surgery (VATS) or a robotic approach. Results: Subsequent to alterations in the procedure, a cohort of 22 patients with an IPN was reviewed. Navigation was possible in 21 out of 22 patients with one patient excluded based on airway anatomy. The remaining 21 patients underwent ENB with pleural dye marking followed by minimally invasive wedge resection. The median size of the nodules was 13.4 mm (range: 7–29). There were no complications from the ENB procedure. Indigo carmine dye was used in ten patients. Methylene blue was used in the remaining 11 patients. In 81% of cases, the visceral pleural marker was visible at the time of surgery. In one patient, there was diffuse staining of the parietal pleura. In three additional patients, no dye was identified within the hemithorax. In all cases where dye marker was present on the visceral pleural surface, it was in proximity to the IPN and part of the excised specimen. Conclusions: ENB with pleural dye marking can provide a safe and effective method to localize an IPN and can allow for subsequent minimally invasive resection. Depending on the characteristics and location of the nodule, this method may allow more rapid identification intraoperatively

Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses