Structure of the dimeric form of CTP synthase from Sulfolobus solfataricus

CTP synthase catalyzes the last committed step in de novo pyrimidine-nucleotide biosynthesis. Active CTP synthase is a tetrameric enzyme composed of a dimer of dimers. The tetramer is favoured in the presence of the substrate nucleotides ATP and UTP; when saturated with nucleotide, the tetramer completely dominates the oligomeric state of the enzyme. Furthermore, phosphorylation has been shown to regulate the oligomeric states of the enzymes from yeast and human. The crystal structure of a dimeric form of CTP synthase from Sulfolobus solfataricus has been determined at 2.5 Å resolution. A comparison of the dimeric interface with the intermolecular interfaces in the tetrameric structures of Thermus thermophilus CTP synthase and Escherichia coli CTP synthase shows that the dimeric interfaces are almost identical in the three systems. Residues that are involved in the tetramerization of S. solfataricus CTP synthase according to a structural alignment with the E. coli enzyme all have large thermal parameters in the dimeric form. Furthermore, they are seen to undergo substantial movement upon tetra­merization

Long-Term Outcome in a Phase II Study of Regional Hyperthermia Added to Preoperative Radiochemotherapy in Locally Advanced and Recurrent Rectal Adenocarcinomas

Hyperthermia was added to standard preoperative chemoradiation for rectal adenocarcinomas in a phase II study. Patients with T3-4 N0-2 M0 rectal cancer or local recurrences were included. Radiation dose was 54 Gy combined with capecitabine 825 mg/m2 × 2 daily and once weekly oxaliplatin 55 mg/m2. Regional hyperthermia aimed at 41.5–42.5 °C for 60 min combined with oxaliplatin infusion. Radical surgery with total or extended TME technique, was scheduled at 6–8 weeks after radiation. From April 2003 to April 2008, a total of 49 eligible patients were recruited. Median number of hyperthermia sessions were 5.4. A total of 47 out of 49 patients (96%) had the scheduled surgery, which was clinically radical in 44 patients. Complete tumour regression occurred in 29.8% of the patients who also exhibited statistically significantly better RFS and CSS. Rate of local recurrence alone at 10 years was 9.1%, distant metastases alone occurred in 25.6%, including local recurrences 40.4%. RFS for all patients was 54.8% after 5 years and CSS was 73.5%. Patients with T50 temperatures in tumours above median 39.9 °C had better RFS, 66.7% vs. 31.3%, p = 0.047, indicating a role of hyperthermia. Toxicity was acceptable.publishedVersio

Phosphorylation of Glutamine Synthetase on Threonine 301 Contributes to Its Inactivation During Epilepsy

The astrocyte-specific enzyme glutamine synthetase (GS), which catalyzes the amidation of glutamate to glutamine, plays an essential role in supporting neurotransmission and in limiting NH4+ toxicity. Accordingly, deficits in GS activity contribute to epilepsy and neurodegeneration. Despite its central role in brain physiology, the mechanisms that regulate GS activity are poorly defined. Here, we demonstrate that GS is directly phosphorylated on threonine residue 301 (T301) within the enzyme’s active site by cAMP-dependent protein kinase (PKA). Phosphorylation of T301 leads to a dramatic decrease in glutamine synthesis. Enhanced T301 phosphorylation was evident in a mouse model of epilepsy, which may contribute to the decreased GS activity seen during this trauma. Thus, our results highlight a novel molecular mechanism that determines GS activity under both normal and pathological conditions.</p

Emergence of Livestock-Associated Methicillin-Resistant Staphylococcus aureus Bloodstream Infections in Denmark

Background Livestock-associated methicillin-resistant Staphylococcus aureus clonal complex 398 (LA-MRSA CC398) is causing an increasing number of skin and soft tissue infections (SSTIs) in Denmark and other European countries with industrial pig production. Yet, its impact on MRSA bloodstream infections (BSIs) has not been well studied. Methods We investigated the clinical epidemiology of all human cases of LA-MRSA CC398 BSI during 2010–2015. Cases of LA-MRSA CC398 BSI were compared to cases of BSI caused by other types of MRSA and cases of SSTI caused by LA-MRSA CC398. Whole-genome sequence analysis was used to assess the phylogenetic relationship among LA-MRSA CC398 isolates from Danish pigs and cases of BSI and SSTI. Results The number of LA-MRSA CC398 BSIs and SSTIs increased over the years, peaking in 2014, when LA-MRSA CC398 accounted for 16% (7/44) and 21% (211/985) of all MRSA BSIs and SSTIs, corresponding to 1.2 and 37.4 cases of BSI and SSTI per 1000000 person-years, respectively. Most patients with LA-MRSA CC398 BSI had no contact to livestock, although they tended to live in rural areas. LA-MRSA CC398 caused 24.3 BSIs per 1000 SSTIs among people with no livestock contact, which is similar to the ratio observed for other types of MRSA. Whole-genome sequence analysis showed that most of the BSI and SSTI isolates were closely related to Danish pig isolates. Conclusions This study demonstrates that the increasing number of LA-MRSA CC398 BSIs occurred in parallel with a much larger wave of LA-MRSA CC398 SSTIs and an expanding pig reservoir

Functional characterization of the first missense variant in <i>CEP78</i>, a founder allele associated with cone-rod dystrophy, hearing loss and reduced male fertility

Inactivating variants in the centrosomal CEP78 gene have been found in cone-rod dystrophy with hearing loss (CRDHL), a particular phenotype distinct from Usher syndrome. Here, we identified and functionally characterized the first CEP78 missense variant c.449T>C, p.(Leu150Ser) in three CRDHL families. The variant was found in a biallelic state in two Belgian families and in a compound heterozygous state-in trans with c.1462-1G>T-in a third German family. Haplotype reconstruction showed a founder effect. Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts. Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly. Two affected males from different families displayed sperm abnormalities causing infertility. One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility. Taken together, our data indicate that a missense founder allele in CEP78 underlies the same sensorineural CRDHL phenotype previously associated with inactivating variants. Interestingly, the CEP78 phenotype has been possibly expanded with male infertility. Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities

PERANAN PELUKIS ADE MOELYANA DALAM MENGEMBANGKAN SENI LUKIS DARI LIMBAH PELEPAH PISANG DI CIMAHI: (Kajian historis dari tahun 1969-2010)

Skripsi ini berjudul “Peranan Pelukis Ade Moelyana Dalam Mengembangkan Seni Lukis Pelepah Pisang di Cimahi Kajian Historis Tahun 1969-2010”. Permasalahan pokok yang dikaji dalam skripsi ini adalah bagaimana perkembangan seni lukis dari limbah pelepah pisang di Cimahi dari tahun 1969-2010 dan keterkaitannya dengan potensi ekonomi dari seni lukis pelepah pisang yang terabaikan. Metode yang digunakan adalah metode historis yang melalui empat tahap yaitu pengumpulan sumber lisan maupun sumber tertulis, kritik, interpretasi, dan historiografi. Untuk memperdalam analisis, penulis menggunakan pendekatan interdisipliner melalui kajian ilmu sosial dan ilmu ekonomi dengan memakai konsep-konsep seperti interaksi sosial, distribusi, ekonomi kreatif, kewirausahaan, dll. Teknik penelitian yang digunakan dalam penelitian ini adalah dengan menggunakan teknik wawancara. Hal ini dilakukan karena terbatasnya sumber tertulis yang mengkaji secara langsung mengenai permasalahan di atas. Berdasarkan hasil temuan di lapangan, seni lukis dari limbah pelepah pisang ini telah ada sejak tahun 1969. Seni lukis ini merupakan seni lukis yang unik karena menggunakan limbah dari pelepah pisang. Pada awal perkembangannya seni lukis ini tidak serta merta dapat diterima oleh masyarakat sekitar, dan barulah pada tahun 2002 seni lukis dari limbah pelepah pisang ini mengalami puncak perkembangan. Pasalnya seni lukis ini tidak hanya dipasarkan di Cimahi saja, melainkan sampai ke mancanegara. Seni lukis dari limbah pelepah pisang ini dapat dijadikan sebagai sektor ekonomi kreatif dan dapat dijadikan sebagai lahan lapangan pekerjaan. Banyak upaya yang dilakukan oleh pelukis untuk mengembangkan seni lukis dari limbah pelepah pisang, selain itu pula pemerintah turut serta dalam mengembangkan seni lukis pelepah pisang. Kata kunci : Seni Lukis Pelepah Pisang, Ekonomi Kreatif, Pemasaran This skripsi titled Ade Moelyama role in developing the art painting of wasted banana leaves in Cimahi of historical studies from 1969 to 2010. The main issue studied in this skripsi was “How Development Art Painting of Wasted Banana Leaves in Cimahi from 1969 to 2010 and linkages with economic potential of art painting of banana leaves neglected. The method used is the historical method through four phases of heuristics, criticism, interpretation and historiography. To deepen the analysis, the author use the approach interdisciplinary through the study of social and economic by using concepts such as social interaction, distribution, creative economy, entrepreneurship, and other. A research technique used in this research is to use interview techniques. This is done because of the limited resources that examines written directly on the above problems. Based on the research results, the art painting of wasted banana leaves has existed since 1969. This painting is a painting that is unique because it uses waste form banan leaves. In the early development of art is not necessarily acceptable to the local community, and then in 2002 the art painting of wasted banana leaves is experiencing the peak development. This is because not only do marketing painting around Cimahi but abroad as well. Painting of wasted banana stalks can be used as a creative economic sector and creates jobs. Lack of awareness of the various parties to make this painting became dormant. Many attempts were made by the painter to develop the art of waste banana leaves, in addition the goverment also participated in the development the art of painting banana leaves. Keywords : Art Painting of Banana Leaves, Creative Economy, Marketin