Comparing Effects of Biologic Agents in Treating Patients with Rheumatoid Arthritis: A Multiple Treatment Comparison Regression Analysis

Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra, rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs.     

Homodimerization and isoform-specific heterodimerization of neuroligins

Neuroligins are postsynaptic adhesion proteins involved in the establishment of functional synapses in the central nervous system. In rodents, four genes give rise to neuroligins that function at distinct synapses, with corresponding neurotransmitter and subtype specificities. In the present study, we examined the interactions between the different neuroligins by isolating endogenous oligomeric complexes using in situ cross-linking on primary neurons. Examining hippocampal, striatal, cerebellar and spinal cord cultures, we found that neuroligins form constitutive dimers, including homomers and, most notably, neuroligin 1/3 heteromers. Additionally, we found that neuroligin monomers are specifically retained in the secretory pathway through a cellular quality control mechanism that involves the neuroligin transmembrane domain, ensuring that dimerization occurs prior to cell surface trafficking. Lastly, we identified differences in the dimerization capacity of autism-associated neuroligin mutants, and found that neuroligin 3 R471C mutants can form heterodimers with neuroligin 1. The pervasive nature of neuroligin dimerization indicates that the unit of neuroligin function is the dimer, and raises intriguing possibilities of distinct heterodimer functions, and of interactions between native and mutant neuroligins contributing to disease phenotypes.     

Do "sperm trading" simultaneous hermaphrodites always trade sperm?

Sperm trading can be a mechanism to solve the conflict oversex roles in hermaphrodites with copulation, sperm competition,and sperm digestion. If present, sperm donation depends on spermreceipt, resulting in conditional reciprocal inseminations.Conditional reciprocity can involve three traded commodities:penis intromissions on a yes-or-no basis, intromission durations(indicating ejaculate size), or sperm transfer. If present,animals that refuse to donate (cheaters) should be desertedby their partner or receive smaller ejaculates. We tested whetherany of these commodities is traded in the simultaneously hermaphroditicsea slug, Chelidonura sandrana. Matings involve a stereotypicsingle sex role alternation. As a result, reciprocity was morefrequent than expected under random mating, supporting tradingof penis intromissions. Contrary to the predictions under tradingof ejaculate sizes, intromission durations were not balancedbetween mating partners. To test trading of sperm transfer itself,we interrupted the sperm groove that transports sperm into thepenis during copulation. Treated animals (experimental cheaters)could still copulate normally but could not transfer sperm.When paired to a cheater, sham-treated control animals did notrespond to the absence of sperm receipt, neither by desertionnor by shortening intromission. We thus reject trading of inseminationdurations and sperm transfer in C. sandrana. Although tradingof intromissions may be present, we discuss why reciprocityin this species may also be a by-product of the mutual willingnessof both partners to donate as well as receive sperm, and notan indicator of sperm trading.     

High-valent [MnFe] and [FeFe] cofactors in ribonucleotide reductases

Ribonucleotide reductases (RNRs) are essential for DNA synthesis in most organisms. In class-Ic RNR from Chlamydia trachomatis (Ct), a MnFe cofactor in subunit R2 forms the site required for enzyme activity, instead of an FeFe cofactor plus a redox-active tyrosine in class-Ia RNRs, for example in mouse (Mus musculus, Mm). For R2 proteins from Ct and Mm, either grown in the presence of, or reconstituted with Mn and Fe ions, structural and electronic properties of higher valence MnFe and FeFe sites were determined by X-ray absorption spectroscopy and complementary techniques, in combination with bond-valence-sum and density functional theory calculations. At least ten different cofactor species could be tentatively distinguished. In Ct R2, two different Mn(IV)Fe(III) site configurations were assigned either L(4)Mn(IV)(μO)(2)Fe(III)L(4) (metal-metal distance of ~2.75?, L = ligand) prevailing in metal-grown R2, or L(4)Mn(IV)(μO)(μOH)Fe(III)L(4) (~2.90?) dominating in metal-reconstituted R2. Specific spectroscopic features were attributed to an Fe(IV)Fe(III) site (~2.55?) with a L(4)Fe(IV)(μO)(2)Fe(III)L(3) core structure. Several Mn,Fe(III)Fe(III) (~2.9-3.1?) and Mn,Fe(III)Fe(II) species (~3.3-3.4?) likely showed 5-coordinated Mn(III) or Fe(III). Rapid X-ray photoreduction of iron and shorter metal-metal distances in the high-valent states suggested radiation-induced modifications in most crystal structures of R2. The actual configuration of the MnFe and FeFe cofactors seems to depend on assembly sequences, bound metal type, valence state, and previous catalytic activity involving subunit R1. In Ct R2, the protonation of a bridging oxide in the Mn(IV)(μO)(μOH)Fe(III) core may be important for preventing premature site reduction and initiation of the radical chemistry in R1.     

Heteronuclear Micro-Helmholtz Coil Facilitates μm-Range Spatial and Sub-Hz Spectral Resolution NMR of nL-Volume Samples on Customisable Microfluidic Chips

We present a completely revised generation of a modular micro-NMR detector, featuring an active sample volume of ∼ 100 nL, and an improvement of 87% in probe efficiency. The detector is capable of rapidly screening different samples using exchangeable, application-specific, MEMS-fabricated, microfluidic sample containers. In contrast to our previous design, the sample holder chips can be simply sealed with adhesive tape, with excellent adhesion due to the smooth surfaces surrounding the fluidic ports, and so withstand pressures of ∼2.5 bar, while simultaneously enabling high spectral resolution up to 0.62 Hz for H₂O, due to its optimised geometry. We have additionally reworked the coil design and fabrication processes, replacing liquid photoresists by dry film stock, whose final thickness does not depend on accurate volume dispensing or precise levelling during curing. We further introduced mechanical alignment structures to avoid time-intensive optical alignment of the chip stacks during assembly, while we exchanged the laser-cut, PMMA spacers by diced glass spacers, which are not susceptible to melting during cutting. Doing so led to an overall simplification of the entire fabrication chain, while simultaneously increasing the yield, due to an improved uniformity of thickness of the individual layers, and in addition, due to more accurate vertical positioning of the wirebonded coils, now delimited by a post base plateau. We demonstrate the capability of the design by acquiring a ¹H spectrum of ∼ 11 nmol sucrose dissolved in D₂O, where we achieved a linewidth of 1.25 Hz for the TSP reference peak. Chemical shift imaging experiments were further recorded from voxel volumes of only ∼ 1.5nL, which corresponded to amounts of just 1.5 nmol per voxel for a 1 M concentration. To extend the micro-detector to other nuclei of interest, we have implemented a trap circuit, enabling heteronuclear spectroscopy, demonstrated by two ¹H/¹³C 2D HSQC experiments.     

New evidence for a tubular structure ofβ-iron(III) oxide hydroxide — akaganéite

A biological method for the preparation of ultrathin transmission electron microscopy (TEM) sections has been used successfully to examine the fragile mineral akaganéite. TEM exposures reveal a tubular structure for akaganéite. The existence of such a structure has been debated for over a decade. The tubular structure may have been active in prebiotic polymerization reactions on the young Earth.     

A model for the conquest of a tree by bark beetles

A model for the interaction between attacking bark beetles and a tree is developed and discussed. It is shown that in addition to the more intuitive outcomes where the tree wins or the beetles win, it is also deduced that under certain conditions there may exist a stable coexistence (at least for some period of time) between the beetles and a living tree. Finally, it is demonstrated that the outcome of the tree-beetle interaction often depends on initial conditions such as the number of colonizing beetles.
These results are discussed with reference to empirical findings, as well as to the development of proper population dynamics models for bark beetles in a forest stand, and models developed for assisting forest managers in avoiding bark beetle outbreaks and for minimizing the damage caused by a bark beetle outbreak.