Certolizumab pegol

Certolizumab pegol (Cimzia^®) is currently the only PEGylated anti-TNFα biologic approved for the treatment of rheumatoid arthritis and Crohn disease. The product, developed by UCB, is a humanized antigen-binding fragment (Fab’) of a monoclonal antibody that has been conjugated to polyethylene glycol. Certolizumab pegol was approved as a treatment for rheumatoid arthritis in the EU, US and Canada in 2009, and as a treatment for Crohn disease in Switzerland in 2007 and the US in 2008. Certolizumab pegol is entering into an increasingly competitive marketplace, especially in rheumatoid arthritis, but clinical data demonstrate benefits across a range of clinical, radiographic and patient reported outcomes.Key words: certolizumab pegol, rheumatoid arthritis, Crohn disease, TNFα, PEGylated, methotrexate     

Exit strategies of intracellular pathogens

The exit of intracellular pathogens from host cells is an important step in the infectious cycle, but is poorly understood. It has recently emerged that microbial exit is a process that can be directed by organisms from within the cell, and is not simply a consequence of the physical or metabolic burden that is imposed on the host cell. This Review summarizes our current knowledge on the diverse mechanisms that are used by intracellular pathogens to exit cells. An integrated understanding of the diversity that exists for microbial exit pathways represents a new horizon in the study of host-pathogen interactions.     

Reversible Control by Vitamin D of Granulocytes and Bacteria in the Lungs of Mice: An Ovalbumin-Induced Model of Allergic Airway Disease

Vitamin D may be essential for restricting the development and severity of allergic diseases and asthma, but a direct causal link between vitamin D deficiency and asthma has yet to be established. We have developed a ‘low dose’ model of allergic airway disease induced by intraperitoneal injection with ovalbumin (1 µg) and aluminium hydroxide (0.2 mg) in which characteristics of atopic asthma are recapitulated, including airway hyperresponsiveness, antigen-specific immunoglobulin type-E and lung inflammation. We assessed the effects of vitamin D deficiency throughout life (from conception until adulthood) on the severity of ovalbumin-induced allergic airway disease in vitamin D-replete and -deficient BALB/c mice using this model. Vitamin D had protective effects such that deficiency significantly enhanced eosinophil and neutrophil numbers in the bronchoalveolar lavage fluid of male but not female mice. Vitamin D also suppressed the proliferation and T helper cell type-2 cytokine-secreting capacity of airway-draining lymph node cells from both male and female mice. Supplementation of initially vitamin D-deficient mice with vitamin D for four weeks returned serum 25-hydroxyvitamin D to levels observed in initially vitamin D-replete mice, and also suppressed eosinophil and neutrophil numbers in the bronchoalveolar lavage fluid of male mice. Using generic 16 S rRNA primers, increased bacterial levels were detected in the lungs of initially vitamin D-deficient male mice, which were also reduced by vitamin D supplementation. These results indicate that vitamin D controls granulocyte levels in the bronchoalveolar lavage fluid in an allergen-sensitive manner, and may contribute towards the severity of asthma in a gender-specific fashion through regulation of respiratory bacteria.     

New evidence for hybrid zones of forest and savanna elephants in Central and West Africa

The African elephant consists of forest and savanna subspecies. Both subspecies are highly endangered due to severe poaching and habitat loss, and knowledge of their population structure is vital to their conservation. Previous studies have demonstrated marked genetic and morphological differences between forest and savanna elephants, and despite extensive sampling, genetic evidence of hybridization between them has been restricted largely to a few hybrids in the Garamba region of northeastern Democratic Republic of Congo (DRC). Here, we present new genetic data on hybridization from previously unsampled areas of Africa. Novel statistical methods applied to these data identify 46 hybrid samples – many more than have been previously identified – only two of which are from the Garamba region. The remaining 44 are from three other geographically distinct locations: a major hybrid zone along the border of the DRC and Uganda, a second potential hybrid zone in Central African Republic and a smaller fraction of hybrids in the Pendjari–Arli complex of West Africa. Most of the hybrids show evidence of interbreeding over more than one generation, demonstrating that hybrids are fertile. Mitochondrial and Y chromosome data demonstrate that the hybridization is bidirectional, involving males and females from both subspecies. We hypothesize that the hybrid zones may have been facilitated by poaching and habitat modification. The localized geography and rarity of hybrid zones, their possible facilitation from human pressures, and the high divergence and genetic distinctness of forest and savanna elephants throughout their ranges, are consistent with calls for separate species classification.     

Construction of physical and genetic maps of Chlamydia trachomatis serovar L2 by pulsed-field gel electrophoresis.

We constructed the physical map of Chlamydia trachomatis serovar L2 by using three restriction endonucleases, NotI (GC[GGCCGC), SgrAI (C(A/G)[CCGG(T/G)G), and Sse8387I (CCTGCA[GG), and we analyzed the fragments by pulsed-field gel electrophoresis. A total of 25 restriction endonuclease sites and 13 genes and/or operons were located on the map. The genome size was determined to be 1,045 kb. Neither highly transcribed chlamydia genes nor developmental cycle-specific genes were clustered on the genome.     

Differential protein synthesis and utilization during cilia formation in sea urchin embryos.

Pulse labeling with [¹⁴C]leucine, hypertonic deciliation, fractionation of axonemes by differential solubilization, and autoradiographic analysis of electrophoretically resolved components reveal that the onset of ciliogenesis is marked by the de novo synthesis of numerous architectural proteins of the “9 + 2” axoneme. The synthesis of most of these components continues, some at reduced rates, after full growth of cilia at hatching. Deciliation results in enhanced synthesis of these minor components, dynein, and tubulin. The A- and B-tubulin dimers, derived from the respective subfibers, have essentially identical specific activities after regeneration in the presence of isotope. Subsequent regeneration in cold leucine demonstrates substantial pools of most of the architectural proteins, but at least two such proteins (nexin and ribbon component-20) are made quantally and in limiting amounts in response to each regeneration. Such second regeneration cilia (whose pools were labeled during the first regeneration) have a decreased specific activity of B-tubulin (10–15%) and an increased specific activity of A-tubulin (30–35%), indicating a limited pool of the former but an apparent retarded synthesis, delayed activation, or initial compartmentalization of the latter. This 45% difference in specific activity of the two tubulin dimer pools offers independent evidence that chemically unique tubulin dimers form the structurally unique subfibers. During natural ciliary augmentation or after stimulation by repeated deciliation, the bulk of the initial incorporation occurs in the quantal, minor components, while newly synthesized dynein and tubulin are not maximally utilized until the succeeding generation. The limited, quantal synthesis of microtubule-associated proteins may be a control mechanism for ciliary assembly or elongation, while a delayed utilization of the major proteins of the axoneme may reflect a replenishment of pools and a requisite activation or post-translational modification of stored components.     

Physical mapping of the von Recklinghausen neurofibromatosis region on chromosome 17

The von Recklinghausen neurofibromatosis (NF1) locus has been linked to chromosome 17, and recent linkage analyses place the gene on the proximal long arm. NF1 probably resides in 17q11.2, since two unrelated NF1 patients have been identified who possess constitutional reciprocal translocations involving 17q11.2 with chromosomes 1 and 22. We have used a somatic-cell hybrid from the t(17;22) individual, along with other hybrid cell lines, to order probes around the NF1 locus. An additional probe, 17L1, has been isolated from a NotI linking library made from flow-sorted chromosome 17 material and has been mapped to a region immediately proximal to the translocation breakpoint. While neither NF1 translocation breakpoint has yet been identified by pulse-field gel analysis, an overlap between two probes, EW206 and EW207, has been detected. Furthermore, we have identified the breakpoint in a non-NF1 translocation, SP-3, on the proximal side of the NF1 locus. This breakpoint has been helpful in creating a 1,000-kb pulsed-field map, which includes the closely linked NF1 probes HHH202 and TH17.19. The combined somatic-cell hybrid and pulsed-field gel analysis we report here favors the probe order D17Z1-HHH202-TH17.19-CRYB1-17L1-NF1- (EW206, EW207, EW203, L581, L946)-(ERBB2, ERBA1). The agreement in probe ordering between linkage analysis and physical mapping is excellent, and the availability of translocation breakpoints in NF1 should now greatly assist the cloning of this locus.