A serine/arginine-rich nuclear matrix cyclophilin interacts with the C-terminal domain of RNA polymerase II

The largest subunit of RNA polymerase II shows a striking difference in the degree of phosphorylation, depending on its functional state: initiating and elongating polymerases are unphosphorylated and highly phosphorylated respectively. Phosphorylation mostly occurs at the C-terminal domain (CTD), which consists of a repetitive heptapeptide structure. Using the yeast two-hybrid system, we have selected for mammalian proteins that interact with the phosphorylated CTD of mammalian RNA polymerase II. A prominent isolate, designated SRcyp/CASP10, specifically interacts with the CTD not only in vivo but also in vitro. It contains a serine/arginine-rich (SR) domain, similar to that found in the SR protein family of pre-mRNA splicing factors, which is required for interaction with the CTD. Most remarkably, the N-terminal region of SRcyp includes a peptidyl-prolyl cis-trans isomerase domain characteristic of immunophilins/cyclophilins (Cyp), a protein family implicated in protein folding, assembly and transport. SRcyp is a nuclear protein with a characteristic distribution in large irregularly shaped nuclear speckles and co-localizes perfectly with the SR domaincontaining splicing factor SC35. Recent independent investigations have provided complementary data, such as an association of the phosphorylated form of RNA polymerase II with the nuclear speckles, impaired splicing in a CTD deletion background and inhibition of in vitro splicing by CTD peptides. Taken together, these data indicate that factors directly or indirectly involved in splicing are associated with the elongating RNA polymerases, from where they might translocate to the nascent transcripts to ensure efficient splicing, concomitant with transcriptio

Prospective, observational practice survey of applied skin care and management of cetuximab-related skin reactions: PROSKIN study.

PURPOSE The study aimed to investigate strategies to prevent and treat cetuximab-induced skin reactions and their perceived effectiveness in patients with metastatic colorectal cancer (mCRC) and recurrent/metastatic squamous cell cancer of the head and neck (SCCHN). METHODS This open-label, prospective observational study was conducted in Switzerland. RESULTS A total of 125 patients were included (n = 91 mCRC, n = 34 SCCHN; mean age 63.3 years; 73.6% males). The frequency of acneiform rash grade ≥ 2 increased from 12.6% at week 2 to 21.7% at week 16. The proportion of patients who reported no skin reaction decreased from 75.6% at week 2 to 43.3% at week 16. The most frequently used skin products at any time of observation were moisturizing (77.6%), lipid-regenerating (56.8%) or urea-containing products (52%), systemic antibiotics (49.6%), and vitamin K1 cream (43.2%). There was no clear effectiveness pattern for all product classes: in given patients, either the product showed no effect at all or a moderate/strong effect, consistently over time. CONCLUSIONS A great variety of low-cost general skin care products were commonly used. According to physician's preference, systemic antibiotics and vitamin K1 cream are an appropriate approach to prevent or treat cetuximab-related skin toxicity

Accumulation of mutations in antibody and CD8 T cell epitopes in a B cell depleted lymphoma patient with chronic SARS-CoV-2 infection

Antibodies against the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can drive adaptive evolution in immunocompromised patients with chronic infection. Here we longitudinally analyze SARS-CoV-2 sequences in a B cell-depleted, lymphoma patient with chronic, ultimately fatal infection, and identify three mutations in the spike protein that dampen convalescent plasma-mediated neutralization of SARS-CoV-2. Additionally, four mutations emerge in non-spike regions encoding three CD8 T cell epitopes, including one nucleoprotein epitope affected by two mutations. Recognition of each mutant peptide by CD8 T cells from convalescent donors is reduced compared to its ancestral peptide, with additive effects resulting from double mutations. Querying public SARS-CoV-2 sequences shows that these mutations have independently emerged as homoplasies in circulating lineages. Our data thus suggest that potential impacts of CD8 T cells on SARS-CoV-2 mutations, at least in those with humoral immunodeficiency, warrant further investigation to inform on vaccine design

Principles of cartilage tissue engineering in TMJ reconstruction

Diseases and defects of the temporomandibular joint (TMJ), compromising the cartilaginous layer of the condyle, impose a significant treatment challenge. Different regeneration approaches, especially surgical interventions at the TMJ's cartilage surface, are established treatment methods in maxillofacial surgery but fail to induce a regeneration ad integrum. Cartilage tissue engineering, in contrast, is a newly introduced treatment option in cartilage reconstruction strategies aimed to heal cartilaginous defects. Because cartilage has a limited capacity for intrinsic repair, and even minor lesions or injuries may lead to progressive damage, biological oriented approaches have gained special interest in cartilage therapy. Cell based cartilage regeneration is suggested to improve cartilage repair or reconstruction therapies. Autologous cell implantation, for example, is the first step as a clinically used cell based regeneration option. More advanced or complex therapeutical options (extracorporeal cartilage engineering, genetic engineering, both under evaluation in pre-clinical investigations) have not reached the level of clinical trials but may be approached in the near future. In order to understand cartilage tissue engineering as a new treatment option, an overview of the biological, engineering, and clinical challenges as well as the inherent constraints of the different treatment modalities are given in this paper

Development of the branchial musculature of the Siberian sturgeon ( Acipenser baerii ) reveals a heterochronic shift during the evolution of acipenseriform cranial muscles

Heterochronic shifts are regarded one of the major evolutionary changes acting on developmental modules and underlying the origin of morphological disparity. Conserved characters, rarely subject to heterochronic shifts during the curse of evolution, in contrast could indicate underlying developmental or functional constraints. Here we use the development of the cranial musculature Siberian sturgeon (Acipenser baerii) as a model to investigate the role of heterochrony during the evolution of the craniofacial system of Actinopterygii. Using histology, fluorescent antibody staining and fast propagation-based phase contrast imaging in combination with 3D-reconstruction we describe the development of the branchial and hypobranchial musculature. We show that the development of the first branchial arch is accelerated compared to other basal-branching actinopterygians leading to a more synchronous development with the hyoid arch. A pattern that could relate to the derived migratory behaviour of the neural crest cells in sturgeons. In contrast, the developmental timing of the more posterior branchial musculature, including the cucullaris muscle in the Siberian sturgeon, appears to be highly conserved compared to other Actinopterygii and even Osteognathostomata. This could indicate the presence of functional or developmental constraints underlying the evolution of the muscles at the head/trunk interface

Epidemiologie de la borreliose de Lyme en Suisse romande. [Epidemiology of Lyme borreliosis in French-speaking Switzerland]

The purpose of this study was to assess the number of cases and the clinical aspects of Lyme borreliosis in French-speaking Switzerland. From July 1996 to December 1997, all laboratories performing serological tests for Lyme borreliosis sent a questionnaire to the treating physicians whenever the tests were positive. In addition, the physicians who diagnosed a case on clinical grounds only were also asked to report these cases. During this period, 1460 positive serological tests were recorded among approximately 10,360 performed (14%). A total of 775 questionnaires were returned (53%). In 3/4 of the cases, the test was ordered because of an acute clinical manifestation or a tick bite. The rest related to chronic symptoms or follow-up. In 504 cases (65%), diagnosis was considered certain or probable. These were erythema migrans in 46%, clinical manifestations of stage II in 33% (26 facial palsy, 20 acute arthritis, 5 benign cutaneous lymphocytoma) and chronic symptoms in 21% (23 acrodermatitis, 26 neuropathies, and 8 arthritis). The adjusted incidence, estimated on the basis of the treating physician's place of residence, ranged from 9/100,000 in Valais to 95/100,000 in Neuchatel. This study indicates that Lyme borreliosis is a diagnosis frequently looked for and established in French-speaking Switzerland. Although erythema migrans is the main clinical manifestation, symptoms of stage II and III indicate that Lyme borreliosis is also responsible for relatively major systemic morbidity

Transcriptional Repression by RING Finger Protein TIF1β That Interacts with the KRAB Repressor Domain of KOX1

Many of the vertebrate zinc finger factors of the Krüppel type (C2H2 zinc fingers) contain in their N-terminus a conserved sequence referred to as the KRAB (Krüppel-associated box) domain that, when tethered to DNA, efficiently represses transcription. Using the yeast two-hybrid system, we have isolated an 835 amino acid RING finger (C3HC4 zinc finger) protein, TIF1β (also named KAP-1), that specifically interacts with the KRAB domain of the human zinc finger factor KOX1/ZNF10. TIF1β, TIF1α, PML and efp belong to a characteristic subgroup of RING finger proteins that contain one or two other Cys/His-rich clusters (B boxes) and a putative coiled-coil in addition to the classical C3HC4 RING finger motif (RBCC configuration). Like TIF1α, TIF1β also contains an additional Cys/His cluster (PHD finger) and a bromorelated domain. When tethered to DNA, TIF1β can repress transcription in transiently transfected mammalian cells both from promoter-proximal and remote (enhancer) positions, similarly to the KRAB domain itself. We propose that TIF1β is a mediator of the transcriptional repression exerted by the KRAB domai