Broad neutralization coverage of HIV by multiple highly potent antibodies

Broadly neutralizing antibodies against highly variable viral pathogens are much sought after to treat or protect against global circulating viruses. Here we probed the neutralizing antibody repertoires of four human immunodeficiency virus (HIV)-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies that neutralize broadly across clades. Many of the new monoclonal antibodies are almost tenfold more potent than the recently described PG9, PG16 and VRC01 broadly neutralizing monoclonal antibodies and 100-fold more potent than the original prototype HIV broadly neutralizing monoclonal antibodies. The monoclonal antibodies largely recapitulate the neutralization breadth found in the corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoprotein gp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement of anti-HIV broadly neutralizing monoclonal antibodies now available reveals that certain combinations of antibodies should offer markedly more favourable coverage of the enormous diversity of global circulating viruses than others and these combinations might be sought in active or passive immunization regimes. Overall, the isolation of multiple HIV broadly neutralizing monoclonal antibodies from several donors that, in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventual design of an effective antibody-based HIV vaccine.     

BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition

Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR-ABL1 (ref. 1) and other oncogenic tyrosine kinases. Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs), which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones.     

Synchronicity of Antarctic temperatures and local solar insolation on orbital timescales

The Milankovitch theory states that global climate variability on orbital timescales from tens to hundreds of thousands of years is dominated by the summer insolation at high northern latitudes. The supporting evidence includes reconstructed air temperatures in Antarctica that are nearly in phase with boreal summer insolation and out of phase with local summer insolation. Antarctic climate is therefore thought to be driven by northern summer insolation. A clear mechanism that links the two hemispheres on orbital timescales is, however, missing. We propose that key Antarctic temperature records derived from ice cores are biased towards austral winter because of a seasonal cycle in snow accumulation. Using present-day estimates of this bias in the 'recorder' system, here we show that the local insolation can explain the orbital component of the temperature record without having to invoke a link to the Northern Hemisphere. Therefore, the Antarctic ice-core-derived temperature record, one of the best-dated records of the late Pleistocene temperature evolution, cannot be used to support or contradict the Milankovitch hypothesis that global climate changes are driven by Northern Hemisphere summer insolation variations.     

Some difficulties of ecological thinking,considered from a critical systems perspective: A plea for critical holism

We probably have simplified matters too much. We tend to talk about systems thinking and practice as if we knew what they are. The fashionable call for “holistic” or “systems” thinking in ecological issues provides a major example. This much is certain: the quest for comprehensiveness, although it represents an epistemologically necessary idea, is not realizable. If we assume that it is realizable, the critical idea underlying the quest will be perverted into its opposite, i.e., into a false pretension to superior knowledge and understanding—a danger of which the environmental movement does not always appear to be sufficiently aware. My question, therefore, is this: How can we deal critically with the fact that our thinking, and hence our knowledge, designs, and actions, cannot possibly be comprehensive, in the sense that we never “comprehend” all that ought to be understood before we pass to judgment and action? What consequences does this fact imply for a critical systems approach to ecological concerns and, ultimately, for our concepts of rationality in general?     

Zur Diskussion über die Homogenität des Erdinnern

Summary According to considerations put forwards byW. Kuhn andA. Rittmann some years ago, it follows that the chemical composition of the interior of the earth must be rather homogeneous; the well-known discontinuity which occurs at 2900 km with respect to the propagation of longitudinal and transverse waves should not be due to a discontinuity of the material composition (not to an iron core). It is due to a continous decrease of the viscosity and thereby of the relaxation time; transverse waves of a period of e.g. 30 seconds will no more be propagated in a material whose relaxation time for tangential stress is below 30 seconds, while the longitudinal waves will suffer a decrease of the velocity at the same time.A criticism put forward byA. Eucken consists in the argument that a material in which the time of relaxation for tangential stress becomes equal to the period of the vibration will exhibit a considerable absorption coefficient for longitudinal waves too. It is now shown that the distance on which the period of vibration and the relaxation time are approximately equal is small compared with the wave length of the seismic waves in question, from which it follows that the resulting absorption of the longitudinal waves too will only be small.A further consideration shows that a mixture of 99 atomic % hydrogen and 1 atomic % of iron is most probably supercritical at a temperature of 5000° abs.A survey of the solubilities in question shows further that the hydrogen present in a mixture of 90% hydrogen and 10% iron should on the strength of the absorption coefficient be completely absorbed by the iron at 5000° abs. and at a total pressure of 2.10⁶ atmospheres.The main argument why the assumption of an iron core inside the earth must be dismissed remains the fact that the present state must be the result of an asymptotic processus which at least in its final phase has occurred under conditions similar to the present conditions of temperature, pressure and viscosity; these latter conditions are far from permitting the processus of sedimentation etc. which would be required.     

Evaluation of oral vaccination against mouse-typhoid in a new animal model

Summary In a simple, new animal model the spread of mouse-typhoid within a mouse-colony was studied and oral vaccination against this disease was evaluated. Live vaccine was superior to inactivated vaccine.